Publications

Prolonged Post-Discontinuation Antibiotic Exposure in Very Low Birth Weight Neonates at Risk for Early-Onset Sepsis

Posted on by Kayla Korzekwinski

Journal of the Pediatric Infectious Diseases Society • May 2021

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Le J, Greenberg RG, Benjamin DK Jr, Yoo Y, Zimmerman KO, Cohen-Wolkowiez M, Wade KC; on behalf of the Administrative Core Committee of the Best Pharmaceuticals for Children Act – Pediatric Trials Network
Premature, very low birth weight neonates are at risk for early-onset sepsis and receive ampicillin and gentamicin post-birth. Antimicrobial stewardship supports short-course antibiotics, but how long antibiotic concentrations remain therapeutic post-last dose is unknown. This study used simulations to examine antibiotic exposures in 34,689 neonates. Therapeutic exposure for ampicillin and gentamicin was evaluated relative to the minimum inhibitory concentration for common pathogens. Ampicillin exposure remains therapeutic long after the last dose. Short-course ampicillin provided therapeutic exposures throughout the typical blood culture incubation period.

Evaluating Site-Level Implementations of the HL7 FHIR Standard to Support eSource Data Exchange in Clinical Research

Posted on by Kayla Korzekwinski

Studies in Health Technology and Informatics • May 2021

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Garza MY, Eisenstein E, Kumar KR, Zimmerman KO, Zozus M
Direct extraction and use of electronic health record (EHR) data is a long-term and multifaceted endeavor. A systematic mapping of study data elements was used to measure the coverage of the Health Level Seven (HL7®) Fast Healthcare Interoperability Resources (FHIR®) standard for a federally sponsored, pragmatic cardiovascular randomized controlled trial (RCT) targeting adults. Researchers evaluated site-level implementations of the HL7® FHIR® standard to investigate study- and site-level differences that could affect coverage and offer insight into the feasibility of a FHIR-based eSource solution for multicenter clinical research.

Racial and Ethnic Diversity in Studies Funded Under the Best Pharmaceuticals for Children Act

Posted on by Kayla Korzekwinski

Pediatrics • May 2021

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Abdel-Rahman SM, Paul IM, Hornik C, Sullivan JE, Wade K, Delmore P, Sharma G, Benjamin DK, Zimmerman KO

The Best Pharmaceuticals for Children Act (BPCA) incentivizes the study of on-patent medicines in children and mandates that the NIH sponsor research on off-patent drugs important to pediatric therapeutics. Failing to enroll cohorts that reflect the pediatric population at large restricts the generalizability of such studies. This investigation evaluates racial and ethnic minority representation among participants enrolled in BPCA-sponsored studies. This study revealed no evidence of racial and ethnic bias in enrollment for pediatric studies conducted with funding from BPCA, fulfilling the legislation’s expectation to ensure adequate representation of all children.

Estimation of Body Fat Percentage for Clinical Pharmacokinetic Studies in Children

Posted on by Kayla Korzekwinski

Clinical and Translational Science • March 2021

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Green TP, Binns HJ, Wu H, Ariza AJ, Perrin EM, Quadri M, Hornik CP, Cohen-Wolkowiez M

Obesity is a prevalent childhood condition and the degree of adiposity is likely to be an important covariate in the pharmacokinetics (PKs) of many drugs. The goal of these studies was to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. Researchers examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically derived techniques. They also conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.

Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • March 2021

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Commander SJ, Wu H, Boakye-Agyeman F, Melloni C, Hornik CD, Zimmerman K, Al-Uzri A, Mendley SR, Harper B, Cohen-Wolkowiez M, Hornik CP
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. Simulated exposure decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.

Population Pharmacokinetics of Olanzapine in Children

Posted on by Kayla Korzekwinski
British Journal of Clinical Pharmacology • February 2021
Maharaj AR, Wu H, Zimmerman KO, Autmizguine J, Kalra R, Al-Uzri A, Sherwin CMT, Goldstein SL, Watt K, Cohen-Wolkowiez M, Hornik CP; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed pediatric dosing scheme. This analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and postmenstrual age (PMA) were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants

Posted on by Kayla Korzekwinski

Clinical Pharmacology & Therapeutics • January 2021

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Salerno SN, Edginton A, Gerhart JG, Laughon MM, Ambalavanan N, Sokol GM, Hornik CD, Stewart D, Mills M, Martz K, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Infants being treated for pulmonary hypertension and prevention or treatment of invasive candidiasis may be given sildenafil with fluconazole concurrently. Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.

Early-onset sepsis in term infants admitted to neonatal intensive care units (2011-2016)

Posted on by Kayla Korzekwinski

Journal of Perinatology • January 2021

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Bech Polcwiartek L, Smith PB, Benjamin DK, Zimmerman KO, Love A, Tiu L, Murray S, Kang P, Ebbesen F, Hagstrøm S, Clark RH, Greenberg RG
This study investigated characteristics of term infants culture-evaluated for early-onset sepsis (EOS) in neonatal intensive care units (NICUs), frequencies of organisms causing EOS, and factors associated with EOS. EOS was most commonly caused by group B Streptococcus. Lower EOS risk was associated with low Apgar score, Cesarean delivery, small for gestational age, prenatal antibiotic exposure, and positive or unknown maternal GBS screening result. Increased risk was associated with prolonged rupture of membranes, maternal age <19 years, vasopressor treatment, and ventilator support.

Population Pharmacokinetics of Metoclopramide in Infants, Children, and Adolescents

Posted on by Kayla Korzekwinski

Clinical and Translational Science • November 2020

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Ge S, Mendley SR, Gerhart JG, Melloni C, Hornik CP, Sullivan JE, Atz A, Delmore P, Tremoulet A, Poindexter BB, Harper B, Payne E, Lin S, Erinjeri J, Cohen-Wolkowiez M, Gonzalez D
Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. The study suggests that a metoclopramide dose as previously recommended for pediatric patients results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux.

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

Posted on by Kayla Korzekwinski

JAMA Pediatrics • October 2020

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Maharaj A, Wu H, Hornik CP, Balevic SJ, Hornik CD, Smith PB, Gonzalez D, Zimmerman KO, Benjamin DK Jr., Cohen-Wolkowiez M
This study sought to define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020).  Concerns were raised regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.