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
Affiliations
John N. Van den Anker
Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC 20010, USA
Susan McCune
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
Pieter Annaert
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium
Gerri R. Baer
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
Yeruk Mulugeta
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
Ramy Abdelrahman
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
Kunyi Wu
Office of Clinical Pharmacology, U.S. Food and Drug Administration, Silver Spring, MD 20993 USA
Kevin M. Krudys
Office of Neurosciences, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
Jeffrey Fisher
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
William Slikker
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
Connie Chen
Health and Environmental Sciences Institute, Washington, DC 20005, USA
Gilbert J. Burckart
Office of Clinical Pharmacology, U.S. Food and Drug Administration, Silver Spring, MD 20993 USA
Karel Allegaert
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium
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.
