Pharmacokinetic and pharmacodynamic principles: unique considerations for optimal design of neonatal clinical trials

Yeung, Cindy Hoi Ting; Verstegen, Ruud H. J.; Greenberg, Rachel; Lewis, Tamorah Rae

doi:10.3389/fped.2023.1345969

Cited by 1 publication

(1 citation statement)

References 53 publications

(33 reference statements)

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“…The selection of the appropriate drug dose is a critical component of a successful neonatal trial, as under-dosing could lead to insufficient drug-to-target exposure and lack of efficacy, while over-dosing could lead to toxicity. 11 Therefore, members of our study team established a first-of-its kind neonatal model of metformin pharmacokinetics to facilitate the design of a drug dosing scheme that will maximize the likelihood of efficacy while minimizing the risk of toxicity. We performed Physiologically Based Pharmacokinetic (PBPK) modeling to identify an appropriate starting dose and scaled a published and qualified adult PBPK model of metformin to an infant population of 3-month-olds, with subsequent use for dose-determination.…”

Section: Methods and Analysismentioning

confidence: 99%

A Safety and Feasibility Trial Protocol of Metformin in Infants after Perinatal Brain Injury

Hutchinson,

Pais,

Edginton

et al. 2024

Preprint

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Introduction: Infants with hypoxic-ischemic encephalopathy (HIE) are at high risk for neurodevelopmental impairment, despite current standards of care. Adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognized as a neurorestorative agent, but, to date, has not been used in infants. Herein, we describe a clinical trial with the aim of demonstrating the safety and feasibility of metformin use to improve neurodevelopmental outcomes in infants with HIE. Methods and Analysis: In collaboration with patient and family stakeholders, we designed a pragmatic clinical trial to assess the safety and feasibility of metformin administration in infants. To determine appropriate dosing of metformin, we performed Physiologically Based Pharmaco-Kinetic (PBPK) modeling after scaling a published adult PBPK model of metformin to an infant population of full-term newborns to 3-month-olds. Based on this PBPK modeling and target drug exposure, we determined an optimal target dose of 25 mg/kg/day. Trial participants will complete baseline bloodwork and then receive 6 weeks of daily metformin at 50% of the target dose (12.5mg/kg). At a mid-study visit, repeat laboratory testing will be done, followed by an additional 6 weeks of metformin at target dosing of 25mg/kg. The final study visit will include repeat labs following therapy at target dosing. Pharmacokinetics of metformin will be evaluated with bloodwork collected at study visits, as well as an optional at-home monitoring sub-study. The incidence of safety events and feasibility measures will be reported using descriptive statistics. Our infant PBPK model will be validated with study samples and the dose for future trials adjusted based on new knowledge about metformin PK in infants. Ethics and Dissemination: Approval of the Boston Children's Hospital Institutional Review Board will be obtained prior to study initiation. Trial oversight will be under the direction of a Data Safety Monitoring Board (DSMB) composed of individuals with the appropriate expertise, including external neonatologists and pharmacologists. Registration: This study has been registered at www.clinicaltrials.gov underNCT06429007..

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Section: Methods and Analysismentioning

confidence: 99%