The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

Abstract

The limit for possible survival after extremely preterm birth has steadily improved and consequently, more premature neonates with increasingly lower gestational age at birth now require care. This specialized care often include intensive pharmacological treatment, yet there is currently insufficient knowledge of gestational age dependent differences in drug metabolism. This potentially puts the preterm neonates at risk of receiving sub-optimal drug doses with a subsequent increased risk of adverse or insufficient drug effects, and often pediatricians are forced to prescribe medication as off-label or even off-science. In this review, we present some of the particularities of drug disposition and metabolism in preterm neonates. We highlight the challenges in pharmacometrics studies on hepatic drug metabolism in preterm and particularly extremely (less than 28 weeks of gestation) preterm neonates by conducting a scoping review of published literature. We find that >40% of included studies failed to report a clear distinction between term and preterm children in the presentation of results making direct interpretation for preterm neonates difficult. We present summarized findings of pharmacokinetic studies done on the major CYP sub-systems, but formal meta analyses were not possible due the overall heterogeneous approaches to measuring the phase I and II pathways metabolism in preterm neonates, often with use of opportunistic sampling. We find this to be a testament to the practical and ethical challenges in measuring pharmacokinetic activity in preterm neonates. The future calls for optimized designs in pharmacometrics studies, including PK/PD modeling-methods and other sample reducing techniques. Future studies should also preferably be a collaboration between neonatologists and clinical pharmacologists.

Anakinra Pilot – a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants

“…There are a few reports of anakinra use in early infancy ( 34 , 35 ), and no reported use from birth or in extremely premature neonates. Indeed, drug development in premature neonates more broadly remains a “blind spot” in pharmacology ( 36 ). We considered dose selection a crucial element of this trial, both for safety reasons but also to ensure prospect of direct benefit to participants.…”

Novel Approaches to Postnatal Prophylaxis to Eliminate Vertical Transmission of HIV

“…25,26 The challenges are even greater for preterm neonates, in whom the maturation timelines of gestational and postnatal age overlap. 27 Thus, the pharmacokinetics of antiretroviral drugs cannot be simply extrapolated from studies in older children, and the optimal dose in neonates must be confirmed through dedicated clinical trials. 28 Studies of neonatal "washout" are an efficient way to gain insight into the neonatal metabolism of drugs before formal neonatal pharmacokinetic dosing trials.…”

Ontogeny of CYP3A and UGT activity in preterm piglets: a translational model for drug metabolism in preterm newborns

“…In recent years, the understanding of drug metabolism in the human pediatric population has considerably progressed, but data on preterm neonates remain scarce ( van den Anker and Allegaert, 2021 ). Since enrollment of this vulnerable pediatric subpopulation in clinical studies is restricted by several factors (e.g., difficulty in obtaining informed parental consent, limited possibilities for repeated sampling, and general lack of pediatric trials), little is known about pharmacokinetics (PK) in preterm neonates (i.e., born before 37 weeks of gestation) ( Mørk et al, 2022 ). Understanding the ADME (absorption, distribution, metabolism, and excretion) of drugs in this population is critical, as these patients often require pharmacological treatment to survive ( Mørk et al, 2022 ).…”

“…Since enrollment of this vulnerable pediatric subpopulation in clinical studies is restricted by several factors (e.g., difficulty in obtaining informed parental consent, limited possibilities for repeated sampling, and general lack of pediatric trials), little is known about pharmacokinetics (PK) in preterm neonates (i.e., born before 37 weeks of gestation) ( Mørk et al, 2022 ). Understanding the ADME (absorption, distribution, metabolism, and excretion) of drugs in this population is critical, as these patients often require pharmacological treatment to survive ( Mørk et al, 2022 ). In addition, the level of prematurity may affect drug-metabolizing enzyme (DME) ontogeny, which is insufficiently assessed in preterm neonates ( Mørk et al, 2022 ).…”