Pharmacokinetics

Metronidazole exposure-response and safety in infants

Posted on by Jeannine Sato

Antimicrobial Agents and Chemotherapy, November 2025

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Randell RL, Balevic SJ, Greenberg RG, Cohen-Wolkowiez M, Smith MJ, Benjamin DK Jr, Bendel C, Bliss JM, Chaaban H, Chhabra R, Dammann CEL, Downey LC, Hornik CD, Hussain N, Laughon MM, Lavery A, Moya F, Saxonhouse M, Sokol GM, Trembath A, Weitkamp J-H, Hornik CP; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

The nitroimidazole antibiotic, metronidazole, is frequently prescribed to infants with serious intra-abdominal infections, and multiple dosing recommendations exist. We sought to evaluate the extent to which metronidazole doses and associated exposures achieved desired efficacy and safety in infants enrolled in the Antibiotic Safety in Infants with Complicated Intra-abdominal Infections (SCAMP) trial (NCT01994993). SCAMP participants received intravenous metronidazole as part of multimodal antimicrobial therapy.

Population Pharmacokinetics to Support Intravenous and Enteral Methadone Dosing in Children

Posted on by Jeannine Sato

Journal of Clinical Pharmacology, January 2026

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Watt KM, Thompson EJ, Lam L, Zimmerman K, Hornik CP, Atz AM, Fernandez A, Hupp SR, Bhatt-Mehta V, Benjamin DK Jr, Anand R, Cohen-Wolkowiez M, Gonzalez D, Smith PB, Capparelli EV; Best Pharmaceuticals for Children Act — Pediatric Trials Network Steering Committee.

Methadone is used in hospitalized children to treat pain and iatrogenic opiate withdrawal. Optimal pediatric dosing for both enteral and intravenous methadone is unknown. We conducted two prospective, multi-center, open-label studies to characterize the pharmacokinetics of methadone in the pediatric population. 

Physiologically Based Pharmacokinetic Modeling of Oxcarbazepine to Characterize Its Disposition in Children with Obesity

Posted on by Jeannine Sato

Journal of Clinical Pharmacology, September 2025

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Maglalang PD, Sinha J, Helfer VE, Edginton A, Zimmerman K, Hornik CD, Muller WJ, Rathore M, Benjamin DK Jr, Chen JY, Anand R, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. 

Oxcarbazepine (OXC) is a second-generation antiseizure medication, effective through its active metabolite, 10-mono-hydroxy derivative (MHD). OXC is used as adjunctive therapy for focal-onset and primary generalized tonic-clonic seizures, with recommended dosing based on age and body weight. This study uses physiologically based pharmacokinetic (PBPK) modeling and leverages pharmacokinetic (PK) data acquired from children enrolled in pragmatic trials to understand dosing and subsequent exposure requirements in children with obesity. 

Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real-World Data

Posted on by Jeannine Sato

Clinical and Translational Science, May 2025

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McCann S, Helfer VE, Balevic SJ, Muller WJ, van den Anker JN, Al-Uzri A, Meyer ML, Anderson SG, Turdalieva S, Edginton AN, Gonzalez D; Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee.

Midazolam has been used as a sedative for hospitalized children on- and off-label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under- or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure. The goal of this study was to use two modeling strategies to evaluate dose-exposure of midazolam in children with and without obesity. 

Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity

Posted on by Jeannine Sato

Journal of Clinical Pharmacology, April 2025

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McCann SM, Wen J, Balevic SJ, Muller WJ, Al-Uzri A, Hornik CD, Meyer ML, Anderson SG, Payne EH, Turdalieva S, Chamberlain JM, Gonzalez D; Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee.

Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing.

Population Pharmacokinetics of Meropenem Across the Adult Lifespan

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • February 2025

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Boutzoukas AE, Balevic SJ, Hemmersbach-Miller M, Winokur PL, Gu K, Chan AW, Cohen-Wolkowiez M, Conrad T, An G, Kirkpatrick CMJ, Swamy GK, Walter EB, Schmader KE, Landersdorfer CB.

This study conducted an opportunistic pharmacokinetic study to evaluate the population pharmacokinetics of meropenem, an antimicrobial commonly used to treat Gram-negative infections in adults of different ages, including older adults, and determined optimal dosing regimens. Meropenem dosing should be based on renal function rather than age. For patients without renal impairment, extended infusion may increase the probability of target attainment.

 

Pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants

Posted on by Kayla Korzekwinski

Cardiology in the Young • January 2025

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Kumar KR, Ciociola EC, Skinner KR, Dixit GM, Alvarez S, Benjamin EK, Faulkner JC, Greenberg RG, Clark RH, Benjamin Jr DK, Hornik CP and Jan Hau Lee

New drugs to target different pathways in pulmonary hypertension have resulted in increased combination therapy, but details of this use in infants are not well described. This large multicenter database study describes the pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants. The study revealed an increased use of combination pulmonary vasodilator therapy, favouring inhaled nitric oxide and sildenafil, yet with considerable practice variation. Further research is needed to determine the optimal combination, sequence, dosing, and disease-specific indications for combination therapy.

Pharmacokinetics of Dexamethasone in Children and Adolescents with Obesity

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • August 2024

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Wen J, McCann S, Balevic S, Muller WJ, Hornik C, Autmizguine J, Anderson SG, Payne EH, Turdalieva S, Gonzalez D., Best Pharmaceuticals for Children Act – Pediatric Trials Network

Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity.

Physiologically-based pharmacokinetic modeling of pantoprazole to evaluate the role of CYP2C19 genetic variation and obesity in the pediatric population

Posted on by Kayla Korzekwinski

CPT: Pharmacometrics & Systems Pharmacology • August 2024

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Thompson EJ, Jeong A, Helfer VE, Shakhnovich V, Edginton A, Balevic SJ, James LP, Collier DN, Anand R, Gonzalez D., Best Pharmaceuticals for Children Act – Pediatric Trials Network

Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. This study explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • August 2024

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McCann S, Helfer VE, Balevic SJ, Hornik CH, Goldstein SL, Autmizguine J, Meyer M, Al-Uzri A, Anderson SG, Payne EH, Turdalieva S, Gonzalez D., Best Pharmaceuticals for Children Act – Pediatric Trials Network

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study.