Drug disposition

Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk

Posted on by Kayla Korzekwinski

Clinical Pharmacology & Therapeutics • May 2022

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Job KM, Dallmann A, Parry S, Saade G, Haas D, Hughes B, Berens P, Chen JY, Fu C, Humphrey K, Hornik C, Balevic S, Zimmerman K, Watt K

Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. This study developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure.

Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis

Posted on by Kayla Korzekwinski

The Journal of Pediatric Pharmacology and Therapeutics • November 2021

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Balevic SJ, Becker ML, Gonzalez D, Funk RS

This study evaluated the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). The data suggest that children who are obese may be routinely under-dosed using current dosing strategies. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity

Posted on by Kayla Korzekwinski

Paediatric Drugs • September 2021

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Maharaj AR, Wu H, Zimmerman KO, Muller WJ, Sullivan JE, Sherwin CMT, Autmizguine J, Rathore MH, Hornik CD, Al-Uzri A, Payne EH, Hornik CP, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Meropenem in Preterm and Term Infants

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • June 2021

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Ganguly S, Edginton A, Gerhart JG, Cohen-Wolkowiez M, Greenberg RG, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee
This study applied physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of the antibiotic meropenem in preterm and term infants. Meropenem is approved by the US Food and Drug Administration for use in pediatric patients, including treating complicated intra-abdominal infections in infants < 3 months of age. The PBPK model-based simulations were performed to evaluate meropenem dosing in the product label for infants < 3 months of age treated for complicated intra-abdominal infections. The PBPK model used supports the meropenem dosing regimens recommended in the product label for infants <3 months of age.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections

Posted on by Kayla Korzekwinski

The Pediatric Infectious Disease Journal • June 2021

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Smith MJ, Boutzoukas A, Autmizguine J, Hudak M, Zinkhan E, Bloom BT, Heresi G, Lavery A, Courtney S, Sokol GR, Cotton CM, Bliss J, Mendley S, Bendel C, Dammann C, Weitkamp JH, Saxonhouse MA, Mundakel GT, Debski J, Lewandowski A, Erinjeri J, Gao J, Benjamin DK, Hornik C, Smith PB, Cohen-Wolkowiez M, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network
In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. One hundred eighty infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3). There were no differences in safety outcomes between antibiotic regimens. Each of the antibiotic regimens are safe in premature infants with cIAI.

The use of supplemental hydrocortisone in the management of persistent pulmonary hypertension of the newborn

Posted on by Kayla Korzekwinski

Journal Perinatology • April 2021

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Aleem S, Robbins C, Murphy B, Elliott S, Akinyemi C, Paredes N, Tolia VN, Zimmerman KO, Goldberg RN, Benjamin DK, Greenberg RG

This study aimed to characterize the association between hydrocortisone receipt and hospital outcomes of infants with persistent pulmonary hypertension of the newborn (PPHN). There was no association between hydrocortisone receipt and death, CLD, or oxygen at discharge in our cohort. Prospective studies are needed to evaluate the effectiveness of hydrocortisone in infants with PPHN.

Use of Electronic Health Records to Identify Exposure-Response Relationships in Critically Ill Children: An Example of Midazolam and Delirium

Posted on by Kayla Korzekwinski

Journal of Pediatric Intensive Care • March 2021

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Zimmerman KO, Spears T, Cobbaert M, Boakye-Agyeman F, Wu H, Cohen-Wolkowiez M, Watt KM, Benjamin DK, Becker ML, Traube C, Smith PB

Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, this study explored the exposure-response relationship between midazolam and delirium in critically ill children.

Comparative safety profile of chloral hydrate versus other sedatives for procedural sedation in hospitalized infants

Posted on by Kayla Korzekwinski

Journal of Neonatal-Perinatal Medicine • June 2020

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Dallefeld SH, Smith PB, Crenshaw EG, Daniel KR, Gilleskie ML, Smith DS, Balevic S, Greenberg RG, Chu V, Clark R, Kumar KR, Zimmerman KO

Given the limited available evidence on chloral hydrate safety in neonatal populations and the discrepancy in chloral hydrate acceptance between the US and other countries, we sought to clarify the safety profile of chloral hydrate compared to other sedatives in hospitalized infants.

Safety, Effectiveness, and Exposure-Response of Micafungin in Infants: Application of an Established Pharmacokinetics Model to Electronic Health Records

Posted on by Kayla Korzekwinski

The Pediatric Infectious Disease Journal • February 2020

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Rivera-Chaparro ND, Ericson J, Wu H, Smith BP, Clark RH, Benjamin DK, Cohen-Wolkowiez M, Greenberg RG
Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. This study used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death, or failure of microbiological clearance.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass

Posted on by Kayla Korzekwinski

Anesthesia & Analgesia • December 2019

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Zimmerman KO, Wu H, Laughon M, Greenberg RG, Walczack R, Schulman SR, Smith PB, Hornik CP, Cohen-Wolkowiez M, Watt KM

Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB.