Adam Frymoyer

All Publications

• Acute kidney injury in neonates with hypoxic ischemic encephalopathy based on serum creatinine decline compared to KDIGO criteria. Pediatric nephrology (Berlin, Germany) Ahn, H. C., Frymoyer, A., Boothroyd, D. B., Bonifacio, S., Sutherland, S. M., Chock, V. Y. 2024

  Abstract

  Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity.A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups.Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI.AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH.

  View details for DOI 10.1007/s00467-024-06287-8

  View details for PubMedID 38326648

  View details for PubMedCentralID 4209658

• Resource Utilization and Costs Associated with Approaches to Identify Infants with Early-Onset Sepsis. MDM policy & practice Guan, G., Joshi, N. S., Frymoyer, A., Achepohl, G. D., Dang, R., Taylor, N. K., Salomon, J. A., Goldhaber-Fiebert, J. D., Owens, D. K. 2024; 9 (1): 23814683231226129

  Abstract

  Objective. To compare resource utilization and costs associated with 3 alternative screening approaches to identify early-onset sepsis (EOS) in infants born at ≥35 wk of gestational age, as recommended by the American Academy of Pediatrics (AAP) in 2018. Study Design. Decision tree-based cost analysis of the 3 AAP-recommended approaches: 1) categorical risk assessment (categorization by chorioamnionitis exposure status), 2) neonatal sepsis calculator (a multivariate prediction model based on perinatal risk factors), and 3) enhanced clinical observation (assessment based on serial clinical examinations). We evaluated resource utilization and direct costs (2022 US dollars) to the health system. Results. Categorical risk assessment led to the greatest neonatal intensive care unit usage (210 d per 1,000 live births) and antibiotic exposure (6.8%) compared with the neonatal sepsis calculator (112 d per 1,000 live births and 3.6%) and enhanced clinical observation (99 d per 1,000 live births and 3.1%). While the per-live birth hospital costs of the 3 approaches were similar-categorical risk assessment cost $1,360, the neonatal sepsis calculator cost $1,317, and enhanced clinical observation cost $1,310-the cost of infants receiving intervention under categorical risk assessment was approximately twice that of the other 2 strategies. Results were robust to variations in data parameters. Conclusion. The neonatal sepsis calculator and enhanced clinical observation approaches may be preferred to categorical risk assessment as they reduce the number of infants receiving intervention and thus antibiotic exposure and associated costs. All 3 approaches have similar costs over all live births, and prior literature has indicated similar health outcomes. Inclusion of downstream effects of antibiotic exposure in the neonatal period should be evaluated within a cost-effectiveness analysis.Of the 3 approaches recommended by the American Academy of Pediatrics in 2018 to identify early-onset sepsis in infants born at ≥35 weeks, the categorical risk assessment approach leads to about twice as many infants receiving evaluation to rule out early-onset sepsis compared with the neonatal sepsis calculator and enhanced clinical observation approaches.While the hospital costs of the 3 approaches were similar over the entire population of live births, the neonatal sepsis calculator and enhanced clinical observation approaches reduce antibiotic exposure, neonatal intensive care unit admission, and hospital costs associated with interventions as part of the screening approach compared with the categorical risk assessment approach.

  View details for DOI 10.1177/23814683231226129

  View details for PubMedID 38293656

  View details for PubMedCentralID PMC10826394

• A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia. The AAPS journal Krzyzanski, W., Wintermark, P., Annaert, P., Groenendaal, F., Şahin, S., Öncel, M. Y., Armangil, D., Koc, E., Battin, M. R., Gunn, A. J., Frymoyer, A., Chock, V. Y., Keles, E., Mekahli, D., van den Anker, J., Smits, A., Allegaert, K. 2023; 26 (1): 4

  Abstract

  The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

  View details for DOI 10.1208/s12248-023-00851-0

  View details for PubMedID 38051395

  View details for PubMedCentralID 7906350

• Rectal administration of tacrolimus protects against post-ERCP pancreatitis in mice. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] Lin, Y. C., Ni, J., Swaminathan, G., Khalid, A., Barakat, M. T., Frymoyer, A. R., Tsai, C. Y., Ding, Y., Murayi, J. A., Jayaraman, T., Poropatich, R., Bottino, R., Wen, L., Papachristou, G. I., Sheth, S. G., Yu, M., Husain, S. Z. 2023

  Abstract

  There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis.C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated.Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery.Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.

  View details for DOI 10.1016/j.pan.2023.09.080

  View details for PubMedID 37778935

• Incidence of Neonatal Hypothermia in the Newborn Nursery and Associated Factors. JAMA network open Dang, R., Patel, A. I., Weng, Y., Schroeder, A. R., Lee, H. C., Aby, J., Frymoyer, A. 2023; 6 (8): e2331011

  Abstract

  Thermoregulation is a key component of well-newborn care. There is limited epidemiologic data on hypothermia in late preterm and term infants admitted to the nursery. Expanding on these data is essential for advancing evidence-based care in a population that represents more than 3.5 million births per year in the US.To examine the incidence and factors associated with hypothermia in otherwise healthy infants admitted to the newborn nursery following delivery.A retrospective cohort study using electronic health record data from May 1, 2015, to August 31, 2021, was conducted at a newborn nursery at a university-affiliated children's hospital. Participants included 23 549 infants admitted to the newborn nursery, from which 321 060 axillary and rectal temperature values were analyzed.Infant and maternal clinical and demographic factors.Neonatal hypothermia was defined according to the World Health Organization threshold of temperature less than 36.5 °C. Hypothermia was further classified by severity (mild: single episode, temperature 36.0-36.4 °C; moderate/severe: persistent or recurrent hypothermia and/or temperature <36.0 °C) and timing (early: all hypothermic episodes occurred within the first 24 hours after birth; late: any episode extended beyond the first 24 hours).Of 23 549 included infants (male, 12 220 [51.9%]), 5.6% were late preterm (35-36 weeks' gestation) and 4.3% were low birth weight (≤2500 g). The incidence of mild hypothermia was 17.1% and the incidence of moderate/severe hypothermia was 4.6%. Late hypothermia occurred in 1.8% of infants. Lower birth weight and gestational age and Black and Asian maternal race and ethnicity had the highest adjusted odds across all classifications of hypothermia. The adjusted odds ratios of moderate/severe hypothermia were 5.97 (95% CI 4.45-8.00) in infants with a birth weight less than or equal to 2500 vs 3001 to 3500 g, 3.17 (95% CI 2.24-4.49) in 35 week' vs 39 weeks' gestation, and 2.65 (95% CI 1.78-3.96) in infants born to Black mothers and 1.94 (95% CI 1.61-2.34) in infants born to Asian mothers vs non-Hispanic White mothers.In this cohort study of infants in the inpatient nursery, hypothermia was common, and the incidence varied by hypothermia definition applied. Infants of lower gestational age and birth weight and those born to Black and Asian mothers carried the highest odds of hypothermia. These findings suggest that identifying biological, structural, and social determinants of hypothermia is essential for advancing evidence-based equitable thermoregulatory care.

  View details for DOI 10.1001/jamanetworkopen.2023.31011

  View details for PubMedID 37642965

• Renal Oxygen Saturations and Acute Kidney Injury in the Preterm Infant with Patent Ductus Arteriosus. American journal of perinatology Rose, L. A., Frymoyer, A., Bhombal, S., Chock, V. Y. 2023

  Abstract

  OBJECTIVE: Decreased near-infrared spectroscopy (NIRS) measures of renal oxygen saturation (Rsat) have identified preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA). NIRS may further identify infants at risk for acute kidney injury (AKI) in a population with concern for hsPDA.DESIGN: Review of infants ≤29 weeks gestation undergoing NIRS and echocardiography due to concern for hsPDA. The hsPDA was defined by two of the following: moderate-large size, left to right shunt, aortic flow reversal, left atrial enlargement. AKI was defined by neonatal modified Kidney Disease Improving Global Outcomes (KDIGO). Rsat and cerebral saturation (Csat), averaged over 1 hour, were evaluated for the 24 hour period around echocardiography.RESULT: Among 77 infants, 29 (38%) had AKI by neonatal modified KDIGO criteria. hsPDA was found on echocardiography in 59 (77%). There were no differences in hsPDA in infants with and without AKI (p=0.1). Rsat was not associated with AKI (p=0.3). Infants on dopamine had less Rsat variability (p<0.01).CONCLUSION: Rsat prior to echocardiography did not discriminate AKI in this cohort of preterm infants at risk for hsPDA, however data may not capture optimal timing of Rsat measurement before AKI.

  View details for DOI 10.1055/a-2130-2269

  View details for PubMedID 37459881

• Impact of Model-Informed Precision Dosing on Achievement of Vancomycin Exposure Targets in Pediatric Patients with Cystic Fibrosis. Pharmacotherapy Frymoyer, A., Schwenk, H. T., Brockmeyer, J. M., Bio, L. 2023

  Abstract

  BACKGROUND: Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin exposure during therapy is essential and area under the curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care.METHODS: Retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13years) or 45 mg/kg/day (≥13years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose-adjustment were based on the MIPD CDS tool predictions with a target 24 hour AUC (AUC24 ) 400-600 mg*hr/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared.RESULTS: Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC24 compared to 39% in the pre-MIPD period (p<0.05). After the first TDM and dose adjustment, target AUC24 achievement was also higher post-MIPD versus pre-MIPD (86% vs 57%; p<0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs post-MIPD 9.5%; p=0.9).CONCLUSION: An MIPD approach implemented within a cloud-based, EHR integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.

  View details for DOI 10.1002/phar.2845

  View details for PubMedID 37401162

• Fewer glucose checks and decreased supplementation using dextrose gel for asymptomatic neonatal hypoglycemia. Journal of perinatology : official journal of the California Perinatal Association Walravens, C., Gupta, A., Cohen, R. S., Kim, J. L., Frymoyer, A. 2023

  Abstract

  OBJECTIVE: Evaluate the impact of a neonatal hypoglycemia (NH) clinical pathway implementing buccal dextrose gel in late preterm and term infants.STUDY DESIGN: Quality improvement study at a children's hospital associated birth center. Number of blood glucose checks, use of supplemental milk, and need for IV glucose were followed for 26-months after implementation of dextrose gel and compared to previous 16-month period.RESULTS: After QI implementation, 2703 infants were screened for hypoglycemia. Of these, 874 (32%) received at least one dose of dextrose gel. Special cause shifts with reductions in mean number of blood glucose checks per infant (pre 6.6 vs. post 5.6), use of supplemental milk (pre 42% vs. post 30%), and need for IV glucose (pre 4.8% vs. post 3.5%) were found.CONCLUSION: Incorporating dextrose gel into a clinical pathway for NH was associated with a sustained reduction in number of interventions, use of supplemental milk and need for IV glucose.

  View details for DOI 10.1038/s41372-023-01638-z

  View details for PubMedID 36871107

• Renal oximetry for early acute kidney injury detection in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia. Pediatric nephrology (Berlin, Germany) Rumpel, J. A., Spray, B. J., Frymoyer, A., Rogers, S., Cho, S., Ranabothu, S., Blaszak, R., Courtney, S. E., Chock, V. Y. 2023

  Abstract

  BACKGROUND: Neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia are at high risk of acute kidney injury (AKI).METHODS: We performed a two-site prospective observational study from 2018 to 2019 to evaluate the utility of renal near-infrared spectroscopy (NIRS) in detecting AKI in 38 neonates with HIE receiving therapeutic hypothermia. AKI was defined by a delayed rate of serum creatinine decline (<33% on day 3 of life,<40% on day 5, and<46% on day 7). Renal saturation (Rsat) and systemic oxygen saturation (SpO2) were continuously measured for the first 96h of life (HOL). Renal fractional tissue oxygen extraction (RFTOE) was calculated as (SpO2-Rsat)/(SpO2). Using renal NIRS, urine biomarkers, and perinatal factors, logistic regression was performed to develop a model that predicted AKI.RESULTS: AKI occurred in 20 of 38 neonates (53%). During the first 96 HOL, Rsat was higher, and RFTOE was lower in the AKI group vs. the no AKI group (P<0.001). Rsat>70% had a fair predictive performance for AKI at 48-84 HOL (AUC 0.71-0.79). RFTOE≤25 had a good predictive performance for AKI at 42-66 HOL (AUC 0.8-0.83). The final statistical model with the best fit to predict AKI (AUC=0.88) included RFTOE at 48 HOL (P=0.012) and pH of the infants' first postnatal blood gas (P=0.025).CONCLUSIONS: Lower RFTOE on renal NIRS and pH on infant first blood gas may be early predictors for AKI in neonates with HIE receiving therapeutic hypothermia. A higher resolution version of the Graphical abstract is available as Supplementary information.

  View details for DOI 10.1007/s00467-023-05892-3

  View details for PubMedID 36786860

• Evaluation of Neonatal and Paediatric Vancomycin Pharmacokinetic Models and the Impact of Maturation and Serum Creatinine Covariates in a Large Multicentre Data Set. Clinical pharmacokinetics Hughes, J. H., Tong, D. M., Faldasz, J. D., Frymoyer, A., Keizer, R. J. 2022

  Abstract

  BACKGROUND AND OBJECTIVE: Infants and neonates present a clinical challenge for dosing drugs with high interindividual variability due to these patients' rapid growth and the interplay between maturation and organ function. Model-informed precision dosing (MIPD), which can account for interindividual variability via patient characteristics and Bayesian forecasting, promises to improve individualized dosing strategies in this complex population. Here, we assess the predictive performance of published population pharmacokinetic models describing vancomycin in neonates and infants, and analyze the robustness of these models in the face of clinical uncertainty surrounding covariate values.METHODS: The predictive precision and bias of nine pharmacokinetic models were compared in a large multi-site data set (N = 2061 patients, 5794 drug levels, 28 institutions) of patients aged 0-365 days. The robustness of model predictions to errors in serum creatinine measurements and gestational age was assessed by using recorded values or by replacing covariate values with 0.3, 0.5 or 0.8 mg/dL or with 40 weeks, respectively.RESULTS: Of the nine models, two models (Dao and Jacqz-Aigrain) resulted in predicted concentrations within 2.5 mg/L or 15% of the measured values for at least 60% of population predictions. Within individual models, predictive performance often 2 differed in neonates (0-4 weeks) versus older infants (15-52 weeks). For preterm neonates, imputing gestational age as 40 weeks reduced the accuracy of model predictions. Measured values of serum creatinine improved model predictions compared to using imputed values even in neonates ≤1 week of age.CONCLUSIONS: Several available pharmacokinetic models are suitable for MIPD in infants and neonates. Availability and accuracy of model covariates for patients will be important for guiding dose decision-making.

  View details for DOI 10.1007/s40262-022-01185-4

  View details for PubMedID 36404388

• Rescaling Creatinine Centiles in Neonates Treated with Therapeutic Hypothermia for Neonatal Encephalopathy. Neonatology Allegaert, K., Mekahli, D., Wintermark, P., Groenendaal, F., Borloo, N., Laenen, A., Annaert, P., Sahin, S., Oncel, M. Y., Chock, V. Y., Armangil, D., Koc, E., Battin, M. R., Frymoyer, A., Keles, E., Smits, A. 2022: 1-3

  View details for DOI 10.1159/000526738

  View details for PubMedID 36183691

• Serum Creatinine Patterns in Neonates Treated with Therapeutic Hypothermia for Neonatal Encephalopathy. Neonatology Keles, E., Wintermark, P., Groenendaal, F., Borloo, N., Smits, A., Laenen, A., Mekahli, D., Annaert, P., Sahin, S., Oncel, M. Y., Chock, V., Armangil, D., Koc, E., Battin, M. R., Frymoyer, A., Allegaert, K. 2022: 1-9

  Abstract

  INTRODUCTION: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postnatal age (PNA) may provide more valuable information in TH neonates.METHODS: Data from seven TH neonates and one non-TH-treated, non-NE control cohorts were pooled in a retrospective study. SCr centiles over PNA, and AKI incidence (definition: SCr ≥0.3 mg/dL within 48 h, or ≥1.5 fold vs. the lowest prior SCr within 7 days) and mortality were calculated. Repeated measurement linear models were applied to SCr trends, modeling SCr on PNA, birth weight or gestational age (GA), using heterogeneous autoregressive residual covariance structure and maximum likelihood methods. Findings were compared to patterns in the control cohort.RESULTS: Among 1,136 TH neonates, representing 4,724 SCr observations, SCr (10th-25th-50th-75th-90th-95th) PNA centiles (day 1-10) were generated. In TH neonates, the AKI incidence was 132/1,136 (11.6%), mortality 193/1,136 (17%). AKI neonates had a higher mortality (37.2-14.3%, p < 0.001). Median SCr patterns over PNA were significantly higher in nonsurvivors (p < 0.01) or AKI neonates (p < 0.001). In TH-treated neonates, PNA and GA or birth weight explained SCr variability. Patterns over PNA were significantly higher in TH neonates to controls (801 neonates, 2,779 SCr).CONCLUSIONS: SCr patterns in TH-treated NE neonates are specific. Knowing PNA-related patterns enable clinicians to better assess kidney function and tailor pharmacotherapy, fluids, or kidney supportive therapies.

  View details for DOI 10.1159/000525574

  View details for PubMedID 35797956

• Oral hymecromone decreases hyaluronan in human study participants. The Journal of clinical investigation Rosser, J. I., Nagy, N., Goel, R., Kaber, G., Demirdjian, S., Saxena, J., Bollyky, J. B., Frymoyer, A. R., Pacheco-Navarro, A. E., Burgener, E. B., Rajadas, J., Wang, Z., Arbach, O., Dunn, C. E., Kalinowski, A., Milla, C. E., Bollyky, P. L. 2022; 132 (9)

  Abstract

  BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSIONAfter 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.

  View details for DOI 10.1172/JCI157983

  View details for PubMedID 35499083

• Epidemiology and trends in neonatal early onset sepsis in California, 2010-2017. Journal of perinatology : official journal of the California Perinatal Association Joshi, N. S., Huynh, K., Lu, T., Lee, H. C., Frymoyer, A. 2022

  Abstract

  OBJECTIVE: This study evaluated patterns of neonatal early onset sepsis (EOS) disease burden to guide approaches to EOS management.STUDY DESIGN: Retrospective cohort.RESULT: A total of 1535 EOS cases were identified amongst 2,872,964 neonates born between 2010 and 2017 at 136 NICUs within the California Perinatal Quality Care Collaborative. EOS incidence was 7.4 per 1000 (E coli: 4.3, GBS: 1.1) in preterm, 0.76 per 1000 (E coli: 0.29, GBS: 0.22) in late preterm, and 0.31 per 1000 (E coli: 0.07, GBS 0.13) in term neonates. There was no significant change in overall incidence, though an increase in E coli (p<0.001) and decrease in GBS (p=0.04) incidence were noted. After adjusting for gestational age, there was no difference in the odds of death by pathogen (p>0.2).CONCLUSION: The overall EOS incidence remained steady in California NICUs from 2010-2017, though an increase in E coli and decrease in GBS EOS incidence was noted.

  View details for DOI 10.1038/s41372-022-01393-7

  View details for PubMedID 35469043

• A Clinical Monitoring Approach for Early Onset Sepsis: A Community Hospital Experience. Hospital pediatrics Bain, L., Sivakumar, D., McCallie, K., Balasundaram, M., Frymoyer, A. 1800

  Abstract

  BACKGROUND: A serial clinical examination approach to screen late preterm and term neonates at risk for early onset sepsis has been shown to be effective in large academic centers, resulting in reductions in laboratory testing and antibiotic use. The implementation of this approach in a community hospital setting has not been reported. Our objective was to adapt a clinical examination approach to our community hospital, aiming to reduce antibiotic exposure and laboratory testing.METHODS: At a community hospital with a level III NICU and >4500 deliveries annually, the pathway to evaluate neonates ≥35 weeks at risk for early onset sepsis was revised to focus on clinical examination. Well-appearing neonates regardless of perinatal risk factor were admitted to the mother baby unit with serial vital signs and clinical examinations performed by a nurse. Neonates symptomatic at birth or who became symptomatic received laboratory evaluation and/or antibiotic treatment. Antibiotic use, laboratory testing, and culture results were evaluated for the 14 months before and 19 months after implementation.RESULTS: After implementation of the revised pathway, antibiotic use decreased from 6.7% (n = 314/4694) to 2.6% (n = 153/5937; P < .001). Measurement of C-reactive protein decreased from 13.3% (n = 626/4694) to 5.3% (n = 312/5937; P < .001). No cases of culture-positive sepsis occurred, and no neonate was readmitted within 30 days from birth with a positive blood culture.CONCLUSIONS: A screening approach for early onset sepsis focused on clinical examination was successfully implemented at a community hospital setting resulting in reduction of antibiotic use and laboratory testing without adverse outcomes.

  View details for DOI 10.1542/hpeds.2021-006058

  View details for PubMedID 34935049

• Standardized Evaluation of Cord Gases in Neonates at Risk for Hypoxic Ischemic Encephalopathy. Hospital pediatrics Blecharczyk, E., Lee, L., Birnie, K., Gupta, A., Davis, A., Van Meurs, K., Bonifacio, S., Frymoyer, A. 2021

  Abstract

  BACKGROUND: Umbilical-cord acidemia may indicate perinatal asphyxia and places a neonate at increased risk for hypoxic ischemic encephalopathy (HIE). Our specific aim was to develop a standardized clinical care pathway, ensuring timely identification and evaluation of neonates with umbilical-cord acidemia at risk for HIE.METHODS: A standardized clinical care pathway to screen inborn neonates ≥36 weeks with abnormal cord blood gases (a pH of ≤7.0 or base deficit of ≥10) for HIE was implemented in January 2016. Abnormal cord blood gases resulted in a direct notification from the laboratory to an on-call physician. Evaluation included a modified Sarnat examination, postnatal blood gas, and standardized documentation. The percentage of neonates in which physician notification, documented Sarnat examination, and postnatal blood gas occurred was examined for 6 months before and 35 months after implementation.RESULTS: Of 203 neonates with abnormal cord gases in the post-quality improvement (QI) period, physician notification occurred in 92%. In the post-QI period, 94% had a documented Sarnat examination, and 94% had postnatal blood gas, compared with 16% and 11%, respectively, of 87 neonates in the pre-QI period. In the post-QI period, of those evaluated, >96% were documented within 4 hours of birth. In the post-QI period, 15 (7.4%) neonates were cooled; 13 were in the NICU at time of identification, but 2 were identified in the newborn nursery and redirected to the NICU for cooling.CONCLUSIONS: A standardized screening pathway in neonates with umbilical-cord acidemia led to timely identification and evaluation of neonates at risk for HIE.

  View details for DOI 10.1542/hpeds.2021-006135

  View details for PubMedID 34854918

• The Term Newborn: Early-Onset Sepsis. Clinics in perinatology Puopolo, K. M., Mukhopadhay, S., Frymoyer, A., Benitz, W. E. 2021; 48 (3): 471-484

  Abstract

  The changing epidemiology of early-onset neonatal sepsis among term infants has required reappraisal of approaches to management of newborn infants at potential risk. As this is now a rare disease, new strategies for reduction in diagnostic testing and empirical treatment have been developed. Adoption and refinement of these strategies should be a priority for all facilities where babies are born.

  View details for DOI 10.1016/j.clp.2021.05.003

  View details for PubMedID 34353576

• A Population Physiologically-Based Pharmacokinetic Model to Characterize Antibody Disposition in Pediatrics and Evaluation of the Model using Infliximab. British journal of clinical pharmacology Chang, H. P., Shakhnovich, V., Frymoyer, A., Funk, R. S., Becker, M. L., Park, K. T., Shah, D. K. 2021

  Abstract

  AIMS: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in pediatric patients, there is a need to develop systems PK models that integrate ontogeny related changes in human physiological parameters.METHODS: A population-based physiological-based PK (PBPK) model to characterize antibody PK in pediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate, and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationship for infliximab.RESULTS: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two pediatric cohorts (n=141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody.CONCLUSION: The pediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in pediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

  View details for DOI 10.1111/bcp.14963

  View details for PubMedID 34189743

• Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia. Seminars in fetal & neonatal medicine McPherson, C., Frymoyer, A., Ortinau, C. M., Miller, S. P., Groenendaal, F., Newborn Brain Society Guidelines and Publications Committee 2021: 101264

  Abstract

  Ensuring comfort for neonates undergoing therapeutic hypothermia (TH) after neonatal encephalopathy (NE) exemplifies a vital facet of neonatal neurocritical care. Physiologic markers of stress are frequently present in these neonates. Non-pharmacologic comfort measures form the foundation of care, benefitting both the neonate and parents. Pharmacological sedatives may also be indicated, yet have the potential to both mitigate and intensify the neurotoxicity of a hypoxic-ischemic insult. Morphine represents current standard of care with a history of utilization and extensive pharmacokinetic data to guide safe and effective dosing. Dexmedetomidine, as an alternative to morphine, has several appealing characteristics, including neuroprotective effects in animal models; robust pharmacokinetic studies in neonates with NE treated with TH are required to ensure a safe and effective standard dosing approach. Future studies in neonates treated with TH must address comfort, adverse events, and long-term outcomes in the context of specific sedation practices.

  View details for DOI 10.1016/j.siny.2021.101264

  View details for PubMedID 34215538

• Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment. EClinicalMedicine Gundersen, J. K., Chakkarapani, E., Jary, S., Menassa, D. A., Scull-Brown, E., Frymoyer, A., Walløe, L., Thoresen, M. 2021; 36: 100892

  Abstract

  Hypothermia-treated and intubated infants with moderate or severe hypoxic-ischemic encephalopathy (HIE) usually receive morphine for sedation and analgesia (SA) during therapeutic hypothermia (TH) and endotracheal ventilation. Altered drug pharmacokinetics in this population increases the risk of drug accumulation. Opioids are neurotoxic in preterm infants. In term infants undergoing TH, the long-term effects of morphine exposure are unknown. We examined the effect of opioid administration during TH on neurodevelopmental outcome and time to extubation after sedation ended.In this prospectively collected population-based cohort of 282 infants with HIE treated with TH (2007-2017), the cumulative opioid dose of morphine and equipotent fentanyl (10-60 µg/kg/h) administered during the first week of life was calculated. Clinical outcomes and concomitant medications were also collected. Of 258 survivors, 229 underwent Bayley-3 neurodevelopmental assessments of cognition, language and motor function at 18-24 months. Multivariate stepwise linear regression analysis was used to examine the relation between cumulative opioid dose and Bayley-3 scores. Three severity-groups (mild-moderate-severe) were stratified by early (<6 h) amplitude-integrated electroencephalography (aEEG) patterns.The cumulative dose of opioid administered as SA during TH was median (IQR) 2121 µg/kg (1343, 2741). Time to extubation was independent of SA dose (p > 0.2). There was no significant association between cumulative SA dose and any of the Bayley-3 domains when analysing the entire cohort or any of the aEEG severity groups.Higher cumulative opioid doses in TH-treated infants with HIE was not associated with worse Bayley-3 scores at 18-24 months of age.The Bristol cooling program was funded by the Children's Medical Research Charity SPARKS managing donations for our research from the UK and US, the UK Moulton Foundation, the Lærdal Foundation for Acute Medicine in Norway and the Norwegian Research Council (JKG).

  View details for DOI 10.1016/j.eclinm.2021.100892

  View details for PubMedID 34308308

  View details for PubMedCentralID PMC8257990

• Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment ECLINICALMEDICINE Gundersen, J. K., Chakkarapani, E., Jary, S., Menassa, D. A., Scull-Brown, E., Frymoyer, A., Walloe, L., Thoresen, M. 2021; 36

  View details for DOI 10.1016/j.eclinm.2021.100892

  View details for Web of Science ID 000668206700043

• Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia. The Journal of pediatrics Rumpel, J., Spray, B. J., Chock, V. Y., Kirkley, M. J., Slagle, C. L., Frymoyer, A., Cho, S. H., Gist, K. M., Blaszak, R., Poindexter, B., Courtney, S. E. 2021

  Abstract

  To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.We performed a multicenter prospective observational study of 64 neonates. Urine was obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin 18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), insulin like growth factor binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO AKI criteria.AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use (median [IQR], 2[0-5] days vs. 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; p=0.012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs only yielded a fair prediction. KIM-1 had the best predictive performance across time points with an AUC (SE) of 0.79 (0.11) at 48 HOL. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 HOL.Urine NGAL, KIM-1, and IL-18 were elevated in neonates with HIE receiving TH who developed AKI. However, wide variability and unclear cut off levels make their clinical utility unclear.

  View details for DOI 10.1016/j.jpeds.2021.08.090

  View details for PubMedID 34547334

• Ampicillin Pharmacokinetics in Peripartum and Laboring Women. American journal of perinatology Judy, A. E., Frymoyer, A., Ansari, J., Drover, D. R., Carvalho, B. 2021

  Abstract

  Ampicillin is used for multiple peripartum indications including prevention of neonatal group beta streptococcus (GBS) and treatment of chorioamnionitis. Despite its widespread use in obstetrics, existing pharmacokinetic data for ampicillin do not address contemporary indications or dosing paradigms for this population. We sought to characterize the pharmacokinetic profile of ampicillin administered to laboring women.Using whole blood dried blood spot sampling technique, maternal blood samples were collected at specified times from 31 women receiving IV ampicillin for peripartum indications. Women received either a 2-g loading dose with 1-g administered every 4 h (GBS), or 2-g every 6 h (chorioamnionitis). Pharmacokinetics were analyzed via a population approach with non-linear mixed-effect modeling.The data were best described by a two-compartment model with first-order elimination, with the following whole blood parameters: central volume of distribution (V1) 75.2 L (95% CI 56.3-93.6), clearance (CL) 82.4 L/h (95% CI 59.7-95.7), inter-compartmental clearance (Q) 20.9 L/h (95% CI 16.2-38.2), and peripheral volume of distribution (V2) 61.1 L (95% CI 26.1-310.5). Inter-patient variation in CL and V1 was large (42.0% and 56.7% respectively). Simulations of standard dosing strategies demonstrated over 98% of women are predicted to achieve an estimated free plasma concentration above MIC 0.5 mcg/mL for more than 50% of the dosing interval.Although large variation in the pharmacokinetics of ampicillin in pregnant women exists, as predicted by our model, current standard dosing strategies achieve adequate exposure for GBS in nearly all patients.

  View details for DOI 10.1055/a-1674-6394

  View details for PubMedID 34670320

• Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Pediatric research Frymoyer, A., Van Meurs, K. P., Drover, D. R., Klawitter, J., Christians, U., Chock, V. Y. 2020

  Abstract

  BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5mg/kg intravenous (i.v.) load then 1.8mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10mg/L) associated with clinical response was examined.RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p<0.05). The median half-life was 39.5h (range 27.2-50.4). An aminophylline loading dose of 7mg/kg followed by 1.6mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known.Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE.As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.Fig. 1INDIVIDUAL PREDICTED THEOPHYLLINE CONCENTRATIONS IN NEONATES WITH HIE RECEIVING HYPOTHERMIA BASED ON THE FINAL PHARMACOKINETIC MODEL AS COMPARED TO THE OBSERVED MEASURED CONCENTRATIONS.: DBS dried blood samples measured as part of a prospective study, plasma samples measured as part of clinical care.Fig. 2Relationship between the average theophylline concentration over the first 24h of treatment (Cavg,24) and (a) change in urine output (∆UOP) 24h after the start of treatment and (b) change in serum creatinine (∆SCr) 48h after the start of treatment.Fig. 3Predicted theophylline concentration-time course after aminophylline using (a) dosing strategy used in clinical care during the study time period (loading dose 5mg/kg, followed by 1.8mg/kg every 6h) and (b) optimized dosing strategy (loading dose 7mg/kg, followed by 1.6mg/kg every 12h). Each dosing strategy was simulated in 3000 neonates using the final population pharmacokinetic model. Solid line represents the median and dashed lines represent the 10th and 90th percentile. Shaded area represents targeted concentration range of 4-10mg/L.

  View details for DOI 10.1038/s41390-020-01140-8

  View details for PubMedID 32919393

• Area Under the Curve Achievement of Once Daily Tobramycin in Children with Cystic Fibrosis during Clinical Care. Pediatric pulmonology Brockmeyer, J. M., Wise, R. T., Burgener, E. B., Milla, C., Frymoyer, A. 2020

  Abstract

  BACKGROUND: The area under the concentration-time curve over 24 hours (AUC24 ) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC24 based approach in children is limited.METHODS: A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC24 was estimated using a traditional log-linear regression approach (LLR). AUC24 was also estimated retrospectively using a pharmacokinetic model-based Bayesian forecasting approach (BF). AUC24 achievement after both approaches were compared.RESULTS: In 77 treatment courses (mean age 12.7 ± 5.0 years), a target AUC24 100-125 mg*h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required ≥3 dose adjustments, and the mean number of drug concentrations measured was 7.1 ± 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias -2.1% [95% CI -3.1 to -1.4]; median precision 7.6% [95% CI 7.1 to 8.2%]). AUC24 estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg*h/L (95% CI 4.8 to 8.0 mg*h/L).CONCLUSIONS: Achievement of a narrow AUC24 target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC24 in children with CF is supported. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ppul.25037

  View details for PubMedID 32827334

• Aminophylline for renal protection in neonatal hypoxic-ischemic encephalopathy in the era of therapeutic hypothermia. Pediatric research Chock, V. Y., Cho, S., Frymoyer, A. 2020

  Abstract

  BACKGROUND: Neonates with hypoxic-ischemic encephalopathy (HIE) frequently develop acute kidney injury (AKI). Aminophylline has been shown to reduce severe renal dysfunction in neonates after perinatal asphyxia. However, the effect of aminophylline on renal function in neonates undergoing hypothermia has not been studied.METHODS: A single-center, retrospective chart review of neonates cooled for moderate/severe HIE who received aminophylline for AKI was conducted to assess changes in urine output (UOP) and serum creatinine (SCr). Comparisons were also made to control neonates matched for hours of life who were cooled but unexposed to aminophylline.RESULTS: Sixteen neonates cooled for HIE received aminophylline starting at 25±14h of life. Within 12h of starting aminophylline, UOP increased by 2.6±1.9mL/kg/h. SCr declined by 0.4±0.2mg/dL in survivors over the first 4 days. When compared to control neonates, UOP increase was greater in the aminophylline group (p<0.001). SCr declined in survivors in both groups, although baseline SCr was higher in the aminophylline group.CONCLUSIONS: Aminophylline use in neonates with HIE undergoing hypothermia was associated with an increase in UOP and a decline in SCr. A randomized trial will be needed to establish a potential renal protective role of aminophylline.IMPACT: The renal protective effect of aminophylline in neonates with HIE has not yet been studied in the context of therapeutic hypothermia.Aminophylline exposure in neonates cooled for HIE was associated with increased UOP and a similar decline in SCr when compared to control infants unexposed to aminophylline.Improved renal function after receiving aminophylline in this observational cohort study suggests the need for future randomized trials to establish the potential benefit of aminophylline in the HIE population undergoing hypothermia.

  View details for DOI 10.1038/s41390-020-0999-y

  View details for PubMedID 32503030

• Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit? Cancers Wojcicki, A. V., Kadapakkam, M., Frymoyer, A., Lacayo, N., Chae, H., Sakamoto, K. M. 2020; 12 (2)

  Abstract

  Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.

  View details for DOI 10.3390/cancers12020441

  View details for PubMedID 32069925

• Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation ANESTHESIA AND ANALGESIA Damian, M. A., Hammer, G. B., Elkomy, M. H., Frymoyer, A., Drover, D. R., Su, F. 2020; 130 (1): 209–16

  View details for DOI 10.1213/ANE.0000000000003761

  View details for Web of Science ID 000502991500038

• Sustainability of a Clinical Examination-Based Approach for Ascertainment of Early Onset Sepsis in Late Preterm and Term Neonates. The Journal of pediatrics Frymoyer, A. n., Joshi, N. S., Allan, J. M., Cohen, R. S., Aby, J. L., Kim, J. L., Benitz, W. E., Gupta, A. n. 2020

  View details for DOI 10.1016/j.jpeds.2020.05.055

  View details for PubMedID 32511960

• Model-Informed Precision Dosing of Vancomycin in Hospitalized Children: Implementation and Adoption at an Academic Children's Hospital. Frontiers in pharmacology Frymoyer, A. n., Schwenk, H. T., Zorn, Y. n., Bio, L. n., Moss, J. D., Chasmawala, B. n., Faulkenberry, J. n., Goswami, S. n., Keizer, R. J., Ghaskari, S. n. 2020; 11: 551

  Abstract

  Model-informed precision dosing (MIPD) can serve as a powerful tool during therapeutic drug monitoring (TDM) to help individualize dosing in populations with large pharmacokinetic variation. Yet, adoption of MIPD in the clinical setting has been limited. Overcoming technologic hurdles that allow access to MIPD at the point-of-care and placing it in the hands of clinical specialists focused on medication dosing may encourage adoption.To describe the hospital implementation and usage of a MIPD clinical decision support (CDS) tool for vancomycin in a pediatric population.Within an academic children's hospital, MIPD for vancomycin was implemented via a commercial cloud-based CDS tool that utilized Bayesian forecasting. Clinical pharmacists were recognized as local champions to facilitate adoption of the tool and operated as end-users. Integration within the electronic health record (EHR) and automatic transmission of patient data to the tool were identified as important requirements. A web-link icon was developed within the EHR which when clicked sends users and needed patient-level clinical data to the CDS platform. Individualized pharmacokinetic predictions and exposure metrics for vancomycin are then presented in the form of a web-based dashboard. Use of the CDS tool as part of TDM was tracked and users were surveyed on their experience.After a successful pilot phase in the neonatal intensive care unit, implementation of MIPD was expanded to the pediatric intensive care unit, followed by availability to the entire hospital. During the first 2+ years since implementation, a total of 853 patient-courses (n = 96 neonates, n = 757 children) and 2,148 TDM levels were evaluated using the CDS tool. For the most recent 6 months, the CDS tool was utilized to support 79% (181/230) of patient-courses in which TDM was performed. Of 26 users surveyed, > 96% agreed or strongly agreed that automatic transmission of patient data to the tool was a feature that helped them complete tasks more efficiently; 81% agreed or strongly agreed that they were satisfied with the CDS tool.Integration of a vancomycin CDS tool within the EHR, along with leveraging the expertise of clinical pharmacists, allowed for successful adoption of MIPD in clinical care.

  View details for DOI 10.3389/fphar.2020.00551

  View details for PubMedID 32411000

  View details for PubMedCentralID PMC7201037

• Serial clinical observation for management of newborns at risk of early-onset sepsis. Current opinion in pediatrics Berardi, A., Bedetti, L., Spada, C., Lucaccioni, L., Frymoyer, A. 2019

  Abstract

  PURPOSE OF REVIEW: Current management approaches for asymptomatic neonates at risk of early onset sepsis remain controversial. Strategies based entirely on clinical observation (SCO, serial clinical observation) have gained consensus.RECENT FINDINGS: We briefly compare different strategies for managing asymptomatic newborns suggested in four high-income countries. Then this review details the existing differences in carrying out the SCO in the United Kingdom, the USA, and Italy; the experiences from the studies performed using the SCO; and open questions regarding this strategy. Advantages and limitations of SCO are also discussed. There is a need to assess which symptoms at birth are more predictive of early onset sepsis and therefore require immediate interventions versus those symptoms that can be monitored and re-evaluated.SUMMARY: SCO strategy may require changes in the processes of newborn care at birthing centers. Nonetheless, SCO is safe and is associated with fewer laboratory evaluations and unnecessary antibiotics. Thoughtful and thorough practices related to the care of all newborns will benefit any birthing centre. VIDEO ABSTRACT:: http://links.lww.com/MOP/A40.

  View details for DOI 10.1097/MOP.0000000000000864

  View details for PubMedID 31851052

• Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model. Critical care medicine Purohit, P. J., Elkomy, M. H., Frymoyer, A., Sutherland, S. M., Drover, D. R., Hammer, G. B., Su, F. 2019

  Abstract

  OBJECTIVES: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model.DESIGN: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole).SETTING: University research laboratory.PATIENTS: None.INTERVENTIONS: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug.MEASUREMENTS AND MAIN RESULTS: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates.CONCLUSIONS: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

  View details for DOI 10.1097/CCM.0000000000003895

  View details for PubMedID 31306179

• Individualized Empiric Vancomycin Dosing in Neonates Using a Model-Based Approach JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY Frymoyer, A., Stockmann, C., Hersh, A. L., Goswami, S., Keizer, R. J. 2019; 8 (2): 97–104

  View details for DOI 10.1093/jpids/pix109

  View details for Web of Science ID 000472809600002

• 4-Methylumbelliferyl glucuronide contributes to hyaluronan synthesis inhibition JOURNAL OF BIOLOGICAL CHEMISTRY Nagy, N., Gurevich, I., Kuipers, H. F., Ruppert, S. M., Marshall, P. L., Xie, B. J., Sun, W., Malkovskiy, A. V., Rajadas, J., Grandoch, M., Fischer, J. W., Frymoyer, A. R., Kaber, G., Bollyky, P. L. 2019; 294 (19): 7864–77

  View details for DOI 10.1074/jbc.RA118.006166

  View details for Web of Science ID 000470153300027

• Management of Chorioamnionitis-Exposed Infants in the Newborn Nursery Using a Clinical Examination-Based Approach. Hospital pediatrics Joshi, N. S., Gupta, A., Allan, J. M., Cohen, R. S., Aby, J. L., Kim, J. L., Benitz, W. E., Frymoyer, A. 2019

  Abstract

  BACKGROUND: Antibiotic use in well-appearing late preterm and term chorioamnionitis-exposed (CE) infants was reduced by 88% after the adoption of a care approach that was focused on clinical monitoring in the intensive care nursery to determine the need for antibiotics. However, this approach continued to separate mothers and infants. We aimed to reduce maternal-infant separation while continuing to use a clinical examination-based approach to identify early-onset sepsis (EOS) in CE infants.METHODS: Within a quality improvement framework, well-appearing CE infants ≥35 weeks' gestation were monitored clinically while in couplet care in the postpartum unit without laboratory testing or empirical antibiotics. Clinical monitoring included physician examination at birth and nurse examinations every 30 minutes for 2 hours and then every 4 hours until 24 hours of life. Infants who developed clinical signs of illness were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, and clinical outcomes were collected.RESULTS: Among 319 initially well-appearing CE infants, 15 (4.7%) received antibiotics, 23 (7.2%) underwent laboratory testing, and 295 (92.5%) remained with their mothers in couplet care throughout the birth hospitalization. One infant had group B Streptococcus EOS identified and treated at 24 hours of age based on new-onset tachypnea and had an uncomplicated course.CONCLUSIONS: Management of well-appearing CE infants by using a clinical examination-based approach during couplet care in the postpartum unit maintained low rates of laboratory testing and antibiotic use and markedly reduced mother-infant separation without adverse events. A framework for repeated clinical assessments is an essential component of identifying infants with EOS.

  View details for PubMedID 30833294

• An Evaluation of Vancomycin Area Under the Curve Estimation Methods for Children Treated for Acute Pulmonary Exacerbations of Cystic Fibrosis Due to Methicillin-Resistant Staphylococcus aureus JOURNAL OF CLINICAL PHARMACOLOGY Stockmann, C., Olson, J., Rashid, J., Lubsch, L., Young, D. C., Hersh, A. L., Frymoyer, A., Ampofo, K., Liu, X., Wang, Y., Sherwin, C. T., Zobell, J. T. 2019; 59 (2): 198–205

  View details for DOI 10.1002/jcph.1323

  View details for Web of Science ID 000456327700005

• Model-Informed Precision Dosing at the Bedside: Scientific Challenges and Opportunities CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY Keizer, R. J., ter Heine, R., Frymoyer, A., Lesko, L. J., Mangat, R., Goswami, S. 2018; 7 (12): 785–87

  View details for DOI 10.1002/psp4.12353

  View details for Web of Science ID 000454530000001

• Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation. Anesthesia and analgesia Damian, M. A., Hammer, G. B., Elkomy, M. H., Frymoyer, A., Drover, D. R., Su, F. 2018

  Abstract

  BACKGROUND: Dexmedetomidine (DEX) is a sedative and analgesic medication that is frequently used postoperatively in children after liver transplantation. Hepatic dysfunction, including alterations in drug clearance, is common immediately after liver transplantation. However, the pharmacokinetics (PK) of DEX in this population is unknown. The objective of this study was to determine the PK profile of DEX in children after liver transplantation.METHODS: This was a single-center, open-label PK study of DEX administered as an intravenous loading dose of 0.5 mug/kg followed by a continuous infusion of 0.5 mug/kg/h. Twenty subjects, 1 month to 18 years of age, who were admitted to the pediatric intensive care unit after liver transplantation were enrolled. Whole blood was collected and analyzed for DEX concentration using a dried blood spot method. Nonlinear mixed-effects modeling was used to characterize the population PK of DEX.RESULTS: DEX PK was best described by a 2-compartment model with first-order elimination. A typical child after liver transplantation with an international normalized ratio (INR) of 1.8 was found to have a whole blood DEX clearance of 52 L/h (95% confidence interval [CI], 31-73 L/h). In addition, intercompartmental clearance was 246 L/h (95% CI, 139-391 L/h), central volume of distribution was 186 L/70 kg (95% CI, 140-301 L/70 kg), and peripheral volume of distribution was 203 L (95% CI, 123-338 L). Interindividual variability ranged from 11% to 111% for all parameters. Clearance was not found to be associated with weight but was found to be inversely proportional to INR. An increase in INR to 3.2 resulted in a 50% decrease in DEX clearance. Weight was linearly correlated with central volume of distribution. All other covariates, including age, ischemic time, total bilirubin, and alanine aminotransferase, were not found to be significant predictors of DEX disposition.CONCLUSIONS: Children who received DEX after liver transplantation have large variability in clearance, which was not found to be associated with weight but is influenced by underlying liver function, as reflected by INR. In this population, titration of DEX dosing to clinical effect may be important because weight-based dosing is poorly associated with blood concentrations. More attention to quality of DEX sedation may be warranted when INR values are changing.

  View details for PubMedID 30198929

• Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia JOURNAL OF PEDIATRICS Chock, V. Y., Frymoyer, A., Yeh, C. G., Van Meurs, K. P. 2018; 200: 232-+

  View details for DOI 10.1016/j.jpeds.2018.04.076

  View details for Web of Science ID 000442390400038

• A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Das, M., Padda, S. K., Frymoyer, A., Molina, J., Adjei, A., Lensing, J. L., Miles, D., Sikic, B. I., Wakelee, H. A. 2018; 82 (3): 541–50

  View details for DOI 10.1007/s00280-018-3646-0

  View details for Web of Science ID 000442431600017

• Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia. The Journal of pediatrics Chock, V. Y., Frymoyer, A., Yeh, C. G., Van Meurs, K. P. 2018

  Abstract

  OBJECTIVE: To investigate the range of renal near-infrared spectroscopy (NIRS) measures in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) and to determine the association between renal NIRS measures and the development of acute kidney injury (AKI).STUDY DESIGN: A retrospective chart review was conducted of neonates with moderate to severe HIE who received therapeutic hypothermia at a tertiary care center from 2014 to 2016. Neonates had routine continuous NIRS monitoring of cerebral and renal saturation (Rsat) as part of their clinical care for 72hours of cooling and until 24hours after rewarming. The outcome of AKI was defined by an abnormal rate of decline of serum creatinine over the first 5 days of life. Mixed effects models determined the association between renal NIRS measures and AKI over time.RESULTS: Of 38 neonates with HIE undergoing cooling, 15 (39%) developed AKI. Rsat was lower than cerebral saturation during cooling (P<.01), but Rsat increased over time after rewarming, while renal oxygen extraction levels decreased (P<.0001). Neonates with AKI had higher Rsat levels (P<.01) compared with those without AKI after 24hours of life. Using receiver operating characteristic curves, Rsat >75% by 24-48hours predicted AKI with a sensitivity of 79% and specificity of 82% (area under the receiver operating characteristic curve=0.76).CONCLUSIONS: Throughout cooling, neonates with AKI had higher Rsat measures than those without AKI. These differences may reflect lower oxygen extraction by the injured kidney. NIRS monitoring of Rsat may identify neonates with HIE at risk of developing AKI.

  View details for PubMedID 29866591

• Clinical Monitoring of Well-Appearing Infants Born to Mothers With Chorioamnionitis PEDIATRICS Joshi, N. S., Gupta, A., Allan, J. M., Cohen, R. S., Aby, J. L., Weldon, B., Kim, J. L., Benitz, W. E., Frymoyer, A. 2018; 141 (4)

  View details for DOI 10.1542/peds.2017-2056

  View details for Web of Science ID 000429276200008

• A Mobile Infliximab Dosing Calculator for Therapy Optimization in Inflammatory Bowel Disease. Inflammatory bowel diseases Piester, T. n., Frymoyer, A. n., Christofferson, M. n., Yu, H. n., Bass, D. n., Park, K. T. 2018; 24 (2): 227–34

  Abstract

  Inadequate infliximab (IFX) drug exposure remains a clinical challenge and leads to high loss of response rates and therapy failure in inflammatory bowel disease (IBD). We aimed to determine the feasibility and pilot effectiveness of a novel, web-based, mobile IFX dosing calculator (mIDC) for therapy optimization.We developed an mIDC leveraging the known clinical variables of C-reative protein (CRP), albumin, patient's weight, disease activity indices, calprotectin, drug trough levels, and antibodies to IFX that significantly affect pharmacokinetics and/or outcomes. A prospective observational cohort study in pediatric and young adult IBD patients receiving maintenance IFX was performed. System-wide practice adoption of mIDC was achieved through a quality improvement (QI) initiative within a hospital-based infusion unit.Forty-nine patients (median age: 16.0 years; 55% female; 65% Crohn's disease) were followed over 9 months. mIDC recommendations for dose optimization were followed by the treating physicians in 198 (89%) out of 222 infusions. Twenty-eight (13%) of 222 mIDC recommendations were to escalate IFX dosing; 15 (54%) of 28 escalation recommendations were declined, and these patients were more likely to already be receiving IFX dose intensification compared with those in whom escalation recommendations were followed (P < 0.05). From mIDC initiation to end of follow-up, mean albumin levels remained unchanged at 3.8 g/dL. Median CRP remained unchanged at 2 g/L. Median calprotectin levels showed a downward trend from 30 to 27 μg/g (n = 9, P < 0.05). The percentage of patients undergoing therapeutic drug monitoring in clinical care increased from 34% to 86% with the QI initiative. The target median IFX trough goal of >5 μg/mL was achieved with 81% probability throughout the QI initiative, an increase of 12% compared with pre-QI values.The use of a novel mIDC is feasible and potentially effective, facilitating both standardization and individualization of therapy in clinical care. mIDC appears to be a practical IFX dosing tool for point-of-care use, leveraging individual pharmacokinetic considerations.

  View details for PubMedID 29361094

• Individualized Empiric Vancomycin Dosing in Neonates Using a Model-Based Approach. Journal of the Pediatric Infectious Diseases Society Frymoyer, A., Stockmann, C., Hersh, A. L., Goswami, S., Keizer, R. J. 2017

  Abstract

  Background: Vancomycin dosing in neonates is challenging because of the large variation in pharmacokinetics. Existing empiric dosing recommendations use table-based formats, within which a neonate is categorized on the basis of underlying characteristics. The ability to individualize dosing is limited because of the small number of "dose categories," and achieving narrow exposure targets is difficult. Our objective was to evaluate a model-based dosing approach (which we designated Neo-Vanco) designed to individualize empiric vancomycin dosing in neonates.Methods: Neo-Vanco was developed on the basis of a published, externally validated population pharmacokinetic model. Using a simulation-based methodology, individualized empiric doses that maximize the probability of attaining a 24-hour area under the curve/minimum inhibitory concentration ratio (AUC24/MIC) of >400 while minimizing troughs >20 mg/L are calculated. To evaluate the Neo-Vanco strategy, retrospective data from neonates treated with vancomycin at 2 healthcare systems were used, and empiric dose recommendations from the following 4 sources were examined: Neo-Vanco, Neofax, Red Book, and Lexicomp. Predicted AUC24 and troughs were calculated and compared.Results: Overall, 492 neonates were evaluated (median postmenstrual age, 36 weeks [5th-95th percentiles (90% range), 25-47 weeks]; median weight, 2.4 kg [90% range, 0.6-4.8 kg]). The percentage of neonates predicted to achieve an AUC24/MIC of >400 was 94% with Neo-Vanco, 18% with Neofax, 23% with Red Book, and 55% with Lexicomp (all P < .0001 vs Neo-Vanco). Predicted troughs of >20 mg/L were infrequent and similar across the dosing approaches (Neo-Vanco, 2.8%; Neofax, 1.0% [P = .03]; Red Book, 2.6% [P = .99]; and Lexicomp, 4.1% [P = .27].Conclusion: A model-based dosing approach that individualizes empiric vancomycin dosing was predicted to improve achievement of target exposure levels in neonates. Prospective clinical evaluation is warranted.

  View details for PubMedID 29294072

• Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Frymoyer, A., Hoekman, D. R., Piester, T. L., de Meij, T. G., Hummel, T. Z., Benninga, M. A., Kindermann, A., Park, K. T. 2017; 65 (6): 639–45

  View details for DOI 10.1097/MPG.0000000000001620

  View details for Web of Science ID 000419723400013

• Early career investigator highlight. Pediatric research Frymoyer, A. 2017; 81 (6): 850-?

  View details for DOI 10.1038/pr.2017.60

  View details for PubMedID 28430775

• Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn's Disease. Journal of pediatric gastroenterology and nutrition Frymoyer, A., Hoekman, D. R., Piester, T. L., de Meij, T. G., Hummel, T. Z., Benninga, M. A., Kindermann, A., Park, K. T. 2017

  Abstract

  The pharmacokinetics of infliximab are highly variable in children with Crohn's disease (CD), and a one-size-fits-all approach to dosing is inadequate. Model-based drug dosing can help individualize dosing strategies. We evaluated the predictive performance and clinical utility of a published population pharmacokinetic model of infliximab in children with CD.Within a cohort of 34 children with CD who had infliximab trough concentrations measured, the pharmacokinetics of each patient was estimated in NONMEM® using a published population pharmacokinetic model. Infliximab concentrations were then predicted based on each patient's dosing history and compared to actual measured concentrations (n = 59). In addition, doses 5-10 mg/kg and dosing intervals every 4-8 weeks were simulated in each patient to examine dose-trough relationships.Predicted concentrations were within ± 1.0 μg/ml of actual measured concentrations for 88% of measurements. The median prediction error (i.e. measure of bias) was -0.15 μg/ml (95%CI: -0.37 to -0.05 μg/ml) and absolute prediction error (i.e. measure of precision) was 0.26 μg/ml (95%CI: 0.15 to 0.40 μg/ml). At standard maintenance dosing of 5 mg/kg every 8 weeks, a trough >3 μg/ml was predicted to be achieved in 32% of patients. To achieve a trough >3 μg/ml, a dosing interval ≤ every 6 weeks was predicted to be required in 29% of patients.A published infliximab population pharmacokinetic model demonstrated accurate predictive performance in a pediatric CD population. Individualized infliximab dosing strategies in children with CD will be critical to consistently achieve trough concentrations associated with optimal outcomes.

  View details for DOI 10.1097/MPG.0000000000001620

  View details for PubMedID 28471911

• Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Bonifacio, S. L., Drover, D. R., Su, F., Wustoff, C. J., Van Meurs, K. P. 2017; 57 (1): 64-76

  Abstract

  Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jcph.775

  View details for PubMedID 27225747

• Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass. Journal of clinical pharmacology Frymoyer, A., Su, F., Grimm, P. C., Sutherland, S. M., Axelrod, D. M. 2016; 56 (9): 1084-1093

  Abstract

  Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age: 5 months [90% range: 1 week - 10 years]) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A one-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in non-cardiac children, theophylline clearance was markedly reduced across age. Applying the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50-75% lower than those recommended in non-cardiac children were needed to achieve target serum concentrations of 5-10 mg/L. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jcph.697

  View details for PubMedID 26712558

• The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clinical and experimental immunology Kuipers, H. F., Nagy, N., Ruppert, S. M., Sunkari, V. G., Marshall, P. L., Gebe, J. A., Ishak, H. D., Keswani, S. G., Bollyky, J., Frymoyer, A. R., Wight, T. N., Steinman, L., Bollyky, P. L. 2016; 185 (3): 372-381

  Abstract

  Recently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan synthesis in mouse models of cancer, autoimmunity, and a variety of other inflammatory disorders where hyaluronan (HA) has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration, and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after one week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a one-week loading period on the drug is required for most protocols. At steady state, over 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulfated metabolite, 4-methylumbelliferyl sulfate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0.65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cei.12815

  View details for PubMedID 27218304

• Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Frymoyer, A., Piester, T. L., Park, K. T. 2016; 62: 723-727

  Abstract

  Standard infliximab maintenance dosing of 5 mg/kg every 8 weeks may be inadequate to consistently achieve sufficient drug exposure to minimize loss of response or treatment failure in pediatric Crohn's disease (CD). We aimed to determine the predicted infliximab trough concentrations in children with CD during maintenance therapy and the percentage of patients achieving target trough concentration >3 μg/ml.A Monte Carlo simulation analysis was constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial. We assessed maintenance dosing strategies of 5, 7.5, and 10 mg/kg at dosing intervals of every 4, 6, and 8 weeks for children that differed by age, weight, albumin level, and concomitant immunomodulator therapy.Based on the index case of a 10 year old with CD receiving standard infliximab dosing with concomitant immunomodulator therapy, the median (IQR) simulated infliximab trough concentration at week 14 was 1.3 (0.5-2.7) μg/ml, and 2.4 (1.0-4.8) μg/ml for albumin levels of 3 and 4 g/dl, respectively. Among 1000 simulated children in the model, trough concentration >3 μg/ml at week 14 was achieved 21% and 41% of the time for albumin levels of 3 and 4 g/dl, respectively.Standard infliximab maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low. Optimized dosing strategies for individual patients are needed to achieve sufficient drug exposure during infliximab maintenance therapy.

  View details for DOI 10.1097/IWPG.0000000000001123

  View details for Web of Science ID 000375334500010

  View details for PubMedID 26890885

• Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery AAPS JOURNAL Elkomy, M. H., Drover, D. R., Glotzbach, K. L., Galinkin, J. L., Frymoyer, A., Su, F., Hammer, G. B. 2016; 18 (1): 124-133

  Abstract

  The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

  View details for DOI 10.1208/s12248-015-9826-5

  View details for Web of Science ID 000367529900010

  View details for PubMedCentralID PMC4706285

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction LUNG CANCER Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280-286

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for DOI 10.1016/j.lungcan.2015.06.011

  View details for Web of Science ID 000360513200010

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction. Lung cancer (Amsterdam, Netherlands) Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280-6

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for DOI 10.1016/j.lungcan.2015.06.011

  View details for PubMedID 26149476

• Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection CLINICAL PHARMACOLOGY & THERAPEUTICS Trachtman, H., Frymoyer, A., Lewandowski, A., Greenbaum, L. A., Feig, D. I., Gipson, D. S., Warady, B. A., Goebel, J. W., Schwartz, G. J., Lewis, K., Anand, R., Patel, U. D. 2015; 98 (1): 25-33

  Abstract

  Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options-including angiotensin-converting enzyme inhibitors-are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2) ), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

  View details for DOI 10.1002/cpt.127

  View details for Web of Science ID 000358502900018

• Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease BIOPHARMACEUTICS & DRUG DISPOSITION Su, F., El-Komy, M. H., Hammer, G. B., Frymoyer, A., Cohane, C. A., Drover, D. R. 2015; 36 (2): 104-114

  Abstract

  Etomidate is a rapid-onset, short-acting hypnotic medication administered for induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants is lacking.The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery.Four neonates and sixteen infants, postnatal age 0.3 - 11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics.The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found to significantly impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 L/min/70-kg and 0.44 L/min/70-kg, respectively; central and peripheral distribution volume of 9.47 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94-142% for all parameters and residual variability was 29%.The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/bdd.1924

  View details for PubMedID 25377074

• 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Frontiers in immunology Nagy, N., Kuipers, H. F., Frymoyer, A. R., Ishak, H. D., Bollyky, J. B., Wight, T. N., Bollyky, P. L. 2015; 6: 123-?

  Abstract

  Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called "hymecromone" where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

  View details for DOI 10.3389/fimmu.2015.00123

  View details for PubMedID 25852691

• Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates. Infectious diseases and therapy Stockmann, C. n., Hersh, A. L., Roberts, J. K., Bhongsatiern, J. n., Korgenski, E. K., Spigarelli, M. G., Sherwin, C. M., Frymoyer, A. n. 2015

  Abstract

  The pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model.A retrospective chart review of neonates who received vancomycin and had ≥1 peak and ≥1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated.A total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23-54) weeks and a median weight of 1.6 (range: 0.4-6.8) kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was -0.8 (95% CI: -1.4 to -0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7-3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed.An evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure.

  View details for DOI 10.1007/s40121-015-0067-9

  View details for PubMedID 25998107

• THE PHARMACOKINETICS OF ETOMIDATE IN NEONATES AND INFANTS WITH CONGENITAL HEART DISEASE Su, F., Cohane, C., Drover, D., El-Komy, M., Frymoyer, A., Hammer, G. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000346211800623

• Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461

  View details for DOI 10.1128/AAC.03620-14

  View details for Web of Science ID 000344158600014

• The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria AAPS JOURNAL Yago, M. R., Frymoyer, A., Benet, L. Z., Smelick, G. S., Frassetto, L. A., Ding, X., Dean, B., Salphati, L., Budha, N., Jin, J. Y., Dresser, M. J., Ware, J. A. 2014; 16 (6): 1358-1365

  View details for DOI 10.1208/s12248-014-9673-9

  View details for Web of Science ID 000344345000023

• Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia THERAPEUTIC DRUG MONITORING Sampson, M. R., Frymoyer, A., Rattray, B., Cotten, C. M., Smith, P. B., Capparelli, E., Bonifacio, S. L., Cohen-Wolkowiez, M. 2014; 36 (5): 584-589

  Abstract

  Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

  View details for Web of Science ID 000342493500005

  View details for PubMedCentralID PMC4166612

• ERLOTINIB (E) AND DOVITINIB (TKI258) (D) IN PATIENTS (PTS) WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A SIGNIFICANT PHARMACOKINETIC (PK) INTERACTION Das, M., Padda, S. K., Zhou, L., Frymoyer, A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1185–S1186

  View details for Web of Science ID 000339624905335

• Gastric Reacidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria MOLECULAR PHARMACEUTICS Yago, M. R., Frymoyer, A. R., Smelick, G. S., Frassetto, L. A., Budha, N. R., Dresser, M. J., Ware, J. A., Benet, L. Z. 2013; 10 (11): 4032-4037

  View details for DOI 10.1021/mp4003738

  View details for Web of Science ID 000326669400009

• Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA Drug-Drug Interaction Potential for Molecular Targeted Agents in Clinical Development MOLECULAR PHARMACEUTICS Smelick, G. S., Heffron, T. P., Chu, L., Dean, B., West, D. A., DuVall, S. L., Lum, B. L., Budha, N., Holden, S. N., Benet, L. Z., Frymoyer, A., Dresser, M. J., Waret, J. A. 2013; 10 (11): 4055-4062

  View details for DOI 10.1021/mp400403s

  View details for Web of Science ID 000326669400012

• Desired Vancomycin Trough Serum Concentration for Treating Invasive Methicillin-resistant Staphylococcal Infections. Pediatric infectious disease journal Frymoyer, A., Guglielmo, B. J., Hersh, A. L. 2013; 32 (10): 1077-1079

  Abstract

  Vancomycin AUC/MIC >400 best predicts outcome when treating invasive MRSA infection, however trough serum concentrations are used clinically to assess the appropriateness of dosing. We used pharmacokinetic modeling and simulation to examine the relationship between vancomycin trough values and AUC/MIC in children receiving vancomycin 15mg/kg every 6h and MRSA MIC of 1 μg/ml. A trough of 7-10 μg/ml predicted achievement of AUC/MIC >400 for >90% of children.

  View details for DOI 10.1097/INF.0b013e318299f75c

  View details for PubMedID 23652479

• Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Journal of perinatology Frymoyer, A., Lee, S., Bonifacio, S. L., Meng, L., LUCAS, S. S., Guglielmo, B. J., Sun, Y., Verotta, D. 2013; 33 (10): 778-782

  Abstract

  To examine the impact of a change in the empiric gentamicin dose from 5 mg kg(-1) every 24 h (Q24 h period) to 5 mg kg every 36 h (Q36 h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24 h period. During the second treatment period (January 2011 to May 2012; n=23), the dose was changed to Q36 h period. Cooling criteria and protocol remained the same between treatment periods. Gentamicin drug concentrations including achievement of target trough concentrations (<2 mg l(-1)) were compared between treatment periods. Individual Bayesian estimates of gentamicin clearance were also compared.Neonates with an elevated trough concentration >2 mg l(-1) decreased from 38 to 4% with implementation of a Q36-h dosing interval (P<0.007). The mean gentamicin trough concentration was 2.0 ± 0.8 mg l(-1) during the Q24 h period and 0.9 ± 0.4 mg l(-1) during the Q36 h period (P<0.001). Peak concentrations were minimally impacted (Q24 h 11.4 ± 2.3 mg l(-1) vs Q36 h 10.0 ± 1.9 mg l(-1); P=0.05). The change in gentamicin trough concentration could not be accounted for by differences in gentamicin clearance between treatment periods (P=0.9).A 5 mg kg(-1) every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2 mg l(-1), while still providing high peak concentration exposure.

  View details for DOI 10.1038/jp.2013.59

  View details for PubMedID 23702622

  View details for PubMedCentralID PMC3762884

• Vancomycin Dosing Practices, Trough Concentrations, and Predicted Area Under the Curve in ChildrenWith Suspected Invasive Staphylococcal Infections JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY Frymoyer, A. 2013; 2 (3): 291–92

  View details for DOI 10.1093/jpids/pit031

  View details for Web of Science ID 000218894200016

• Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy Frymoyer, A., Meng, L., Bonifacio, S. L., Verotta, D., Guglielmo, B. J. 2013; 33 (7): 718-726

  Abstract

  STUDY OBJECTIVE: To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations. DESIGN: Population pharmacokinetic study using retrospective medical record data. SETTING: Tertiary neonatal intensive care unit. PATIENTS: A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring MEASUREMENT AND MAIN RESULTS: Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3 kg, serum creatinine 0.9 mg/dl), clearance was 0.034 L/hour/kg and volume was 0.52 L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5 mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than 90% of neonates. CONCLUSIONS: Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.

  View details for DOI 10.1002/phar.1263

  View details for PubMedID 23553582

• Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Verotta, D., Jacobson, P., Long-Boyle, J. 2013; 75 (2): 463-475

  Abstract

  To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK.Unbound MPA concentration-time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min(-1)), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h(-1) (37.4%), 541 l h(-1) (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK.In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.

  View details for DOI 10.1111/j.1365-2125.2012.04372.x

  View details for Web of Science ID 000313554200017

  View details for PubMedID 22765258

• Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy? CLINICAL PHARMACOLOGY & THERAPEUTICS Budha, N. R., Frymoyer, A., Smelick, G. S., Jin, J. Y., Yago, M. R., Dresser, M. J., Holden, S. N., Benet, L. Z., Ware, J. A. 2012; 92 (2): 203-213

  Abstract

  A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).

  View details for DOI 10.1038/clpt.2012.73

  View details for Web of Science ID 000306596300017

  View details for PubMedID 22739140

• Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women AIDS Dong, B. J., Zheng, Y., Hughes, M. D., Frymoyer, A., Verotta, D., Lizak, P., Sawe, F., Currier, J. S., Lockman, S., Aweeka, F. T. 2012; 26 (7): 833-841

  Abstract

  To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa.In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/μl randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity.NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations.Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/μl (P = 0.003).In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/μl was significantly associated with NVP toxicity.

  View details for DOI 10.1097/QAD.0b013e328351a521

  View details for Web of Science ID 000302813000008

  View details for PubMedID 22301417

• Impact of a Hospitalwide Increase in Empiric Pediatric Vancomycin Dosing on Initial Trough Concentrations PHARMACOTHERAPY Frymoyer, A., Guglielmo, B. J., Wilson, S. D., Scarpace, S. B., Benet, L. Z., Hersh, A. L. 2011; 31 (9): 871-876

  Abstract

  To evaluate the impact of a hospitalwide increase in the recommended vancomycin starting dose from 45 to 60 mg/kg/day on initial vancomycin trough concentrations in children suspected of having an invasive methicillin-resistant Staphylococcus aureus (MRSA) infection.Retrospective medical record review.Dedicated children's hospital located in a tertiary care, academic medical center.A total of 182 children aged 1 month-12 years with normal renal function who had suspected MRSA infections treated with vancomycin during two different starting dose recommendation periods: 45 mg/kg/day divided every 8 hours during July 2006-June 2007 (low-dose group [88 children]) and 60 mg/kg/day divided every 6 hours during July 2008-June 2009 (high-dose group [94 children]).Data on patient demographics, vancomycin doses, and initial vancomycin trough concentrations were collected. No significant demographic differences were noted between patients in the low-dose and high-dose groups. The mean ± SD initial vancomycin trough level increased from 7 ± 5 μg/ml in the low-dose group to 9 ± 5 μg/ml in the high-dose group (p<0.001). The percentage of patients with an initial trough level less than 5 μg/ml declined from 38% (33/88 children) in the low-dose group to 17% (16/94 children) in the high-dose group (p<0.001), whereas the percentage of patients with an initial trough concentration in the potentially adverse range (> 20 μg/ml) did not change between the two groups (2% vs 2%, p=0.9). Less than 14% (13/94 children) achieved a trough level in the range of 15-20 μg/ml in the high-dose group.An increase in the recommended vancomycin starting dose to 60 mg/kg/day decreased the likelihood of an initial low vancomycin trough level (< 5 μg/ml), with no increase in the proportion of patients with trough levels in a potentially toxic range. The 60-mg/kg/day dose did not consistently achieve a vancomycin trough of 15-20 μg/ml, a goal suggested by some experts for adults. Comparative effectiveness studies are needed to directly evaluate vancomycin dosing regimens and clinical outcomes for children with invasive MRSA infections.

  View details for Web of Science ID 000295749400007

  View details for PubMedID 21923588

• Effect of Single-Dose Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers CLINICAL PHARMACOLOGY & THERAPEUTICS Frymoyer, A., Shugarts, S., Browne, M., Wu, A. H., Frassetto, L., Benet, L. Z. 2010; 88 (4): 540-547

  Abstract

  Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the nonspecific organic anion-transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers to examine the in vivo relevance of OATP hepatic uptake on the pharmacokinetics of warfarin. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5-mg dose of warfarin, either alone or immediately following a 600-mg intravenous dose of rifampin. Rifampin did not significantly alter the R- or S-warfarin area under the concentration-time curves (AUCs) from 0 to 12 h (period of hepatic OATP inhibition by rifampin) or the maximum plasma concentration (C(max)) value. AUC(0-∞) was decreased on days rifampin was administered, for both R-warfarin (25% reduction; P < 0.001) and S-warfarin (15% reduction; P < 0.05). No differences were seen in the area under the international normalized ratio (INR)-time curve. Our study suggests that hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin.

  View details for DOI 10.1038/clpt.2010.142

  View details for Web of Science ID 000282064000027

  View details for PubMedID 20703222

• Prediction of Vancomycin Pharmacodynamics in Children With Invasive Methicillin-Resistant Staphylococcus aureus Infections: A Monte Carlo Simulation CLINICAL THERAPEUTICS Frymoyer, A., Hersh, A. L., Coralic, Z., Benet, L. Z., Guglielmo, B. J. 2010; 32 (3): 534-542

  Abstract

  Due to the emergence of community-associated strains, the prevalence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections has increased substantially in pediatric patients. A vancomycin AUC(0-24)/MIC index >400 best predicts treatment outcomes for invasive MRSA infection in adults. Data on whether recommended vancomycin doses in children achieve this break point are lacking.This study aimed to assess the likelihood that currently recommended vancomycin doses in children achieve AUC(0-24)/MIC >400.Vancomycin AUC(0-24)/MIC predictions were conducted across a range of dosages (40-70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC(0-24) was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. Three literature-reported estimates in children were used to define vancomycin clearance and its variance. For the MIC distribution of MRSA isolates, susceptibility data were obtained from the University of California, San Francisco Children's Hospital, San Francisco, California (n = 180; 40% < or =0.5 mg/L; 59% = 1 mg/L; and 1% = 2 mg/L).Using the recommended empiric dosage of 40 mg/kg/d, 58% to 66% of children were predicted to achieve AUC(0-24)/MIC >400. Increasing the vancomycin dosage to 60 mg/kg/d substantially increased the likelihood (88%-98%) of achieving this pharmacodynamic target. On sensitivity analysis, a dosage of 40 mg/kg/d was more strongly influenced by small changes in MIC compared with 60 mg/kg/d.Recommended empiric vancomycin dosing in children (40 mg/kg/d) was not predicted to consistently achieve the pharmacodynamic target of AUC(0-24)/MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.

  View details for DOI 10.1016/j.clinthera.2010.03.005

  View details for Web of Science ID 000276632600010

  View details for PubMedID 20399990

• Current Recommended Dosing of Vancomycin for Children With Invasive Methicillin-Resistant Staphylococcus aureus Infections Is Inadequate PEDIATRIC INFECTIOUS DISEASE JOURNAL Frymoyer, A., Hersh, A. L., Benet, L. Z., Guglielmo, B. J. 2009; 28 (5): 398-402

  Abstract

  Vancomycin area-under-the-concentration-time-curve (AUC) for 24 hours divided by the minimum inhibitory concentration (MIC) (AUC24/MIC) >400 optimally treats invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in adults. It is unknown whether recommended vancomycin dosing regimens for children achieve this value.AUC24/MIC was calculated in children using vancomycin doses of 40 and 60 mg/kg/d. AUC24 was calculated as daily dose/vancomycin clearance. Vancomycin clearance in children was estimated by 2 approaches: (1) previously literature-reported vancomycin clearance, and (2) calculated vancomycin clearance using previously derived predictor models and a hypothetical population of healthy children. Representative MIC of hospital MRSA isolates was used (0.5, 1.0, and 2.0 microg/mL).The MIC50/90 for pediatric MRSA isolates in the previous year was 1.0 microg/mL. With a dose of 40 mg/kg/d, both approaches consistently predicted AUC24/MIC <400 when MIC was 1.0 microg/mL. At 60 mg/kg/d, AUC24/MIC >400 was more readily achieved when MIC was 1.0 microg/mL, however, an MIC of 2.0 microg/mL resulted in AUC24/MIC <400 for both dosing regimens.A vancomycin dose of 40 mg/kg/d in children is unlikely to achieve the recommended pharmacodynamic target of AUC24/MIC >400 for invasive MRSA infections even when MIC is 1.0 microg/mL. A starting dose of 60 mg/kg/d should be used in settings where isolates with MIC of 1.0 are common. Alternatives to vancomycin should strongly be considered for patients with MIC > or =2.0 microg/mL.

  View details for DOI 10.1097/INF.0b013e3181906e40

  View details for Web of Science ID 000265619400008

  View details for PubMedID 19295465

  View details for PubMedCentralID PMC3101254

• Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers JOURNAL OF PAIN Frymoyer, A. R., Rowbotham, M. C., Petersen, K. L. 2007; 8 (1): 19-25

  Abstract

  In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain.Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.

  View details for DOI 10.1016/j.jpain.2006.05.010

  View details for Web of Science ID 000244025700003

  View details for PubMedID 17113353