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

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.

Effects of the Off-Label Drug Prescription in the Paediatric Population in Spain from the Adoption of the Latest European Regulation: A Pre-Post Study

“…Some diseases are unique to neonates, but others could be similar (or not) to other population groups, which adds complexity to this end. In addition, several factors should be considered for specific drug dosing approaches, as maturational pharmacokinetics and body size, which play a unique role in this subpopulation group [ 26 ].…”

Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates

“…Although, such data do not exist in preterm neonates, available evidence on cord plasma concentrations of methadone-exposed term and preterm neonates did not show any significant difference [17]. Furthermore, in view of a lack of data specific to preterm neonates, extrapolation of data is unavoidable to expand the evidence required to optimize the care of such vulnerable populations [39]. Our assumption for initiation of pharmacologic treatment in preterm neonates with umbilical cord methadone concentration of less than 60 ng/mL has to be prospectively studied and validated.…”

Amikacin or Vancomycin Exposure Alters the Postnatal Serum Creatinine Dynamics in ELBW Neonates

“…There are numerous reasons why approval of drugs for use in (pre)term neonates is still lagging behind. A major issue is the more difficult demonstration of efficacy and safety, as this commonly needs assessment tools tailored to this population [1][2][3]. Related to safety and adverse events, this includes assessment of seriousness, causality and severity within the framework of regulatory requirements [1,3].…”