Pharmacokinetics

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit

Posted on by Kayla Korzekwinski

The Pediatric Infectious Disease Journal • June 2024

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Wade KC, Greenberg RG, Benjamin DK Jr., Chen L, Vo B, Ang BL, Boutzoukas A, Zimmerman KO, Clark RH, Cohen-Wolkowiez M, Le J on behalf of the Administrative Core Committee of the Best Pharmaceuticals for Children Act – Pediatric Trials Network

In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • June 2024

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Maglalang PD, Sinha J, Zimmerman K, McCann S, Edginton A, Hornik CP, Hornik CD, Muller WJ, Al-Uzri A, Meyer M, Chen L, Anand R, Perrin E, Gonzalez D., Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee

Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.

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.

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

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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.

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.