Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs.

John N Van Den Anker,Yeruk Mulugeta,Susan Mccune,Ramy Abdelrahman,Jeffrey Fisher,William Slikker,Gerri R Baer,Connie Chen,Karel Allegaert,Kevin M Krudys,Gilbert J Burckart,Pieter Annaert,Kunyi Wu

doi:10.3390/pharmaceutics12070685

Abstract

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

Highlights

Health-care providers still frequently use dosing regimens and drug formulations that initially were developed for adults or children in neonates
These legal initiatives have been critically important as the survival of extremely low birth weight infants continues to increase and most of these infants are exposed to medications that are used “off-label”, meaning that these drugs are not FDA- or European Medicines Agency (EMA) approved for use in neonates [10,11]
The results indicated that administration of lucinactant increased gas exchange and decreased ventilator pressure in premature monkeys while the monkeys receiving colfosceril showed little or no improvement [63]

Summary

Introduction

Health-care providers still frequently use dosing regimens and drug formulations that initially were developed for adults or children in neonates. In the U.S, the incentives of the Best Pharmaceuticals for Children Act (BPCA) in 2002 and the requirements of the Pediatric Research Equity Act (PREA) in 2003 provided a regulatory framework for the study and approval of new drugs in relevant pediatric populations [4,5] These Acts were made permanent under the 2012 FDA Safety and Innovation Act (FDASIA). In Europe, neonates were included at the initiation of the Pediatric Regulation in 2007 and an EMA Guideline on the Investigation of Medicinal Products in Term and Preterm Neonates was released the same year [8,9] These legal initiatives have been critically important as the survival of extremely low birth weight infants continues to increase and most of these infants are exposed to medications that are used “off-label”, meaning that these drugs are not FDA- or EMA approved for use in neonates [10,11]

Objectives

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Discussion

Conclusion