Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

CPT Pharmacometrics & Systems Pharmacology • November 2018.

Ku LC, Hornik CP, Beechinor RJ, Chamberlain JM, Guptill JT, Harper B, Capparelli EV, Martz K, Anand R, Cohen-Wolkowiez M, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice.

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A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents

Pediatric Drugs • October 2018.

Shakhnovich V, Brian Smith P, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act–Pediatric Trials Network.

Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers.

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Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children

The Journal of Clinical Pharmacology • April 2018.

Hornik CP, Gonzalez D, van den Anker J, Atz AM, Yogev R, Poindexter BB, Ng KC, Delmore P, Harper BL, Melloni C, Lewandowski A, Gelber C, Cohen-Wolkowiez M, Lee JH; Pediatric Trial Network Steering Committee.

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown.

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Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

The Journal of Pediatrics • February 2018.

Shakhnovich V, Smith PB, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL; Best Pharmaceuticals for Children Act – Pediatric Trials Network.

To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula.

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Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Antimicrobial Agents and Chemotherapy • December 2017.

Autmizguine J, Melloni C, Hornik CP, Dallefeld S, Harper B, Yogev R, Sullivan JE, Atz AM, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D; the Pediatric Trials Network Steering Committee.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children.

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Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Clinical Pharmacokinetics • August 2017.

Gonzalez D, Chamberlain JM, Guptill JT, Cohen-Wolkowiez M, Harper B, Zhao J, Capparelli EV; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE.

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Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Antimicrobial Agents and Chemotherapy • March 2017.

Smith MJ, Gonzalez D, Goldman JL, Yogev R, Sullivan JE, Reed MD, Anand R, Martz K, Berezny K, Benjamin DK Jr, Smith PB, Cohen-Wolkowiez M, Watt K; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size.

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Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

The Journal of Clinical Pharmacology • March 2016.

Estepp JH, Melloni C, Thornburg CD, Wiczling P, Rogers Z, Rothman JA, Green NS, Liem R, Brandow AM, Crary SE, Howard TH, Morris MH, Lewandowski A, Garg U, Jusko WJ, Neville KA; Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee.

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia; however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU.

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Gaps in Drug Dosing for Obese Children: A Systematic Review of Commonly Prescribed Emergency Care Medications

Clinical Therapy • September 2015.

Rowe S, Siegel D, Benjamin DK Jr; Best Pharmaceuticals for Children Act – Pediatric Trials Network Administrative Core Committee.

Approximately 1 of 6 children in the United States is obese. This has important implications for drug dosing and safety because pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiologic mechanisms. Inappropriate drug dosing in an emergency setting can limit therapeutic efficacy and increase drug-related toxic effects for obese children.

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Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review

JAMA Peds • July 2015.

Harskamp-van Ginkel MW, Hill KD, Becker KC, Testoni D, Cohen-Wolkowiez M, Gonzalez D, Barrett JS, Benjamin DK Jr, Siegel DA, Banks P, Watt KM; Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee.

Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity’s effect on drug safety, pharmacokinetics, and dosing in obese children is unknown.

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