Bio

Clinical Focus


  • Pediatrics
  • Infant, Newborn

Honors & Awards


  • Clinical Pharmacologist, NICHD Pediatric Trials Network (2010-)
  • Presidential Trainee Award, American Society for Clinical Pharmacology and Therapeutics (2010)
  • Doris Duke Clinical Research Scholar, Doris Duke Charitable Foundation (2001-02)
  • Junior Elected Member, Alpha Omega Alpha Honor Medical Society (2003)
  • Cum Laude (M.D.), University of Pittsburgh (2004)
  • The President's Freshman Award, Penn State University (1996)
  • Honors (B.S.), Penn State University (1999)

Professional Education


  • Fellowship:Univ of California San Francisco (2009) CA
  • Board Certification: Pediatrics, American Board of Pediatrics (2007)
  • Residency:Univ of California San Francisco (2007) CA
  • Medical Education:University of Pittsburgh School of Medicine (2004) PA

Research & Scholarship

Current Research and Scholarly Interests


Improve the safety and effectiveness of medicines used in children through the application of clinical pharmacokinetics and pharmacodynamics to quantitatively guide pediatric therapeutic decision-making.

Publications

Journal Articles


  • 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

  • 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

  • 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

    Objective: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.Study Design: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.Result: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).Conclusion: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.Journal of Perinatology advance online publication, 23 May 2013; doi:10.1038/jp.2013.59.

    View details for DOI 10.1038/jp.2013.59

    View details for PubMedID 23702622

  • 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

  • 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/?l 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/?l (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/?l 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 ?g/ml in the low-dose group to 9 ± 5 ?g/ml in the high-dose group (p<0.001). The percentage of patients with an initial trough level less than 5 ?g/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 ?g/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 ?g/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 ?g/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 ?g/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

  • 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

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