The Utility of Pharmacometric Models in Clinical Pharmacology Research in Infants

Abstract

Purpose of commentary: Acquiring knowledge on drug disposition and action in infant is challenging because of the problem of sparse and unbalanced data obtained for each individual infant due to the limited blood volume as well as the issue of extensive inter-subject and intra-subject variability in drug exposure and response due to the fast growth and dynamic maturation changes in infants. This commentary highlights the importance of using population-based pharmacometric models to improve knowledge on drug disposition and action in infants.

Recent findings: Pharmacometric modeling remains to be critical in clinical pharmacology research in infants. Many pediatric covariate models developed for scaling of drug clearance use a combination of allometric weight scaling to account for size change and a sigmoid function of antenatal development and postnatal maturation to characterize the age-related maturation. To expedite the development of safe and effective dosing regimens in infants, a number of strategies have been proposed recently, including the use of pediatric covariate model obtained from one drug for extrapolation to other drugs undergoing similar elimination pathways, as well as the combination of opportunistic clinical studies and population-based pharmacometrics models.

Summary: Population-based pharmacometric modeling plays a pivotal role in clinical pharmacology research in infants. Most of the covariate models reported so far focus on antibiotics undergoing renal elimination. Novel modeling strategies have been proposed recently to facilitate clinical pharmacology research and expedite the dose optimization process in infants.

Keywords: Pharmacometric modeling; erythropoietin pharmacokinetics; infant; opportunistic clinical study; pediatric covariate model; population pharmacokinetics.

Figure 1.

Reference covariate model for characterizing clearance of drugs that are primarily eliminated through kidneys in infants. BW, body weight; PWR, power coefficient; CL, clearance; GA, gestational age; PNA, postnatal age; SCr, serum creatinine. Adapted from Wilbaux et al. JCP 2016.

Figure 2.

a) Final TMDD model describing the PK of Epo. This model characterizes the distribution of Epo between a central compartment (Cp, Vp), and a peripheral compartment (Ct, Vt) determined by a distribution clearance (Q). Epo in the central compartment interacts with Epo receptors (R) with a second-order association rate constant (kon) to form a Epo-R complex (RC). The complex can dissociate back to free Epo and free Epo receptors with a first-order dissociation rate constant (koff). Epo can be eliminated either from the central compartment via a linear pathway (CL) or via internalization of the Epo-R complex (kint). b) Key equations used to characterize the TMDD model; and c) Time courses of observed (symbols) and the final population pharmacokinetic model predicted (lines) Epo plasma concentrations in four representative neonates receiving multiple i.v. and s.c. dose regimens during the first 4 weeks of life. The observed Epo concentration data were obtained from scavenged plasma samples. Adapted from D’Cunha et al. EJPS 2019.