Drug disposition

Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • April 2024

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Randell RL, Balevic SJ, Greenberg RG, Cohen-Wolkowiez M, Thompson EJ, Venkatachalam S, Smith MJ, Bendel C, Bliss JM, Chaaban H, Chhabra R, Dammann CEL, Downey LC, Hornik C, Hussain N, Laughon MM, Lavery A, Moya F, Saxonhouse M, Sokol GM, Trembath A, Weitk

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants study.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity

Posted on by Kayla Korzekwinski

The Journal of Pediatric Pharmacology and Therapeutics • December 2023

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Zimmerman KO, Wu H, Maharaj A, Turner A, Chen L, Hornik CD, Arnold S, Muller W, Al-Uzri A, Meyer M, Shiloh-Malawsky Y, Taravath S, Lakhotia A, Joshi C, Jackman J, Hornik CP; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network

This study sought to characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

Posted on by Kayla Korzekwinski

Contemporary Clinical Trials Communications • December 2022

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Lang JE, Hornik CD, Martz K, Jacangelo J, Anand R, Greenberg R, Hornik C, Zimmerman K, Smith PB, Benjamin DK, Laughon M
Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to many complications. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. We developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD.

Use of Real-World Data and Physiologically-Based Pharmacokinetic Modeling to Characterize Enoxaparin Disposition in Children With Obesity

Posted on by Kayla Korzekwinski

Clinical Pharmacology & Therapeutics • August 2022

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Gerhart JG, Carreño FO, Loop MS, Lee CR, Edginton AN, Sinha J, Kumar KR, Kirkpatrick CM, Hornik CP, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low-molecular-weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. The study aimed to answer this clinical question. Enoxaparin exposure was better matched across age groups and obesity status using fat-free mass weight-based dosing.

Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease

Posted on by Kayla Korzekwinski

Early Human Development • July 2022

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Ericson J, Benjamin DK Jr., Boakye-Agyeman F, Balevic SJ, Cotten MC, Adler-Shohet F, Laughon M, Poindexter B, Harper B, Payne EH, Kaneshige K, Smith PB; Best Pharmaceuticals for Children Act – Pediatric Trials Network
Neonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991. This study aimed to determine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir and examine the association between acyclovir dose and exposure with adverse events (AEs). The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure. Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • January 2023

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

Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults.

Methylprednisolone for Heart Surgery in Infants – A Randomized, Controlled Trial

Posted on by Kayla Korzekwinski

The New England Journal of Medicine • December 2022

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Hill KD, Kannankeril PJ, Jacobs JP, Baldwin HS, Jacobs ML, O’Brien SM, Bichel DP, Graham EM, Blasiole B, Resheidat A, Husain AS, Kumar SR, Kirchner JL, Gallup DS, Turek JW, Bleiweis M, Mettler B, Benscoter A, Wald E, Karamlou T, Van Bergen AH, Overman D

Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. This study was a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database.

Ampicillin dosing in premature infants for early-onset sepsis: exposure-driven efficacy, safety, and stewardship

Posted on by Kayla Korzekwinski

Journal of Perinatology • July 2022

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Le J, Greenberg RG, Yoo Y, Clark RH, Benjamin DK Jr., Zimmerman KO, Cohen-Wolkowiez M, Wade K
This study simulated ampicillin concentrations in newborns to define optimal ampicillin dosing for empiric early-onset sepsis (EOS) therapy in preterm neonates. For EOS in preterm infants, two ampicillin doses (50 mg/kg) provided optimal bactericidal exposures, while minimizing potential toxicity.

Use of physiologically-based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity

Posted on by Kayla Korzekwinski

CPT: Pharmacometrics & Systems Pharmacology • June 2022

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Gerhart JG, Carreno FO, Ford JL, Edginton AN, Perrin EM, Watt KM, Muller WJ, Atz AM, Al-Uzri A, Delmore P, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, there is limited information to guide fentanyl and methadone dosing in these children. This study addresses the clinical knowledge gap using physiologically-based pharmacokinetic models of fentanyl and methadone developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics.

External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data

Posted on by Kayla Korzekwinski

Frontiers in Pharmacology • March 2022

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Karatza E, Ganguly S, Hornik CD, Muller MJ, Al-Uzri A, James L, Balevic SJ, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.