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

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

doi:10.3390/pharmaceutics12070685

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

Pharmaceutics. 2020 Jul 20;12(7):685. doi: 10.3390/pharmaceutics12070685.

Authors

John N Van den Anker^{1

2

3}, Susan McCune⁴, Pieter Annaert⁵, Gerri R Baer⁴, Yeruk Mulugeta⁶, Ramy Abdelrahman⁶, Kunyi Wu⁷, Kevin M Krudys⁸, Jeffrey Fisher⁹, William Slikker⁹, Connie Chen¹⁰, Gilbert J Burckart⁷, Karel Allegaert^{5

11

12}

Affiliations

¹ Division of Clinical Pharmacology, Children's National Hospital, Washington, DC 20010, USA.
² Pediatric Pharmacology and Pharmacometrics Research Center, University Children's Hospital Basel, University of Basel, 4056 Basel, Switzerland.
³ Intensive Care and Department of Pediatric Surgery, Erasmus MC/Sophia Children's Hospital, 3000 CA Rotterdam, The Netherlands.
⁴ Office of Pediatric Therapeutics, Office of Clinical Policy and Programs, Office of the Commissioner, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
⁵ Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.
⁶ Division of Pediatric and Maternal Health, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
⁷ Office of Clinical Pharmacology, U.S. Food and Drug Administration, Silver Spring, MD 20993 USA.
⁸ Office of Neurosciences, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
⁹ National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
¹⁰ Health and Environmental Sciences Institute, Washington, DC 20005, USA.
¹¹ Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
¹² Department of Clinical Pharmacy, Erasmus MC Rotterdam, 3000 CA, The Netherlands.

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.

Keywords: dose finding; drug development; neonatal clinical pharmacology; newborn; pediatric drug delivery.