Causes and Consequences of Variability in Drug Transporter Activity in Pediatric Drug Therapy

Abstract

Drug transporters play a key role in mediating the uptake of endo-and exogenous substances into cells as well as their efflux. Therefore, variability in drug transporter activity can influence pharmaco-and toxicokinetics and be a determinant of drug safety and efficacy. In children, particularly in neonates and young infants, the contribution of tissue-specific drug transporters to drug absorption, distribution, and excretion may differ from that in adults. In this review 5 major factors and their interdependence that may influence drug transporter activity in children are discussed: developmental differences, genetic polymorphisms, pediatric comorbidities, interacting comedication, and environmental factors. Even if data are sparse, altered drug transporter activity due to those factors have been associated with clinically relevant differences in drug disposition, efficacy, and safety in pediatric patients. Single nucleotide polymorphisms in drug transporter-encoding genes were the most studied source of drug transporter variability in children. However, in the age group where drug transporter activity has been reported to differ from that in adults, namely neonates and young infants, hardly any studies have been performed. Longitudinal studies in this young population are required to investigate the age-and disease-dependent genotypephenotype relationships and relevance of drug transporter drug-drug interactions. Physiologically based pharmacokinetic modeling approaches can integrate drug-and patient-specific parameters, including drug transporter ontogeny, and may further improve in silico predictions of pediatric-specific pharmacokinetics.

Pediatric Ontogeny: Moving From Translational Science to Drug Development

“…8 Similarly, the effects of transporters in pediatric PBPK models have been addressed. 9 Therefore, the pediatric clinical and translational science community should renew their efforts to fill in the gaps in knowledge in pediatric ontogeny and drug disposition based on emerging therapies. Some of that information may come from basic science, but critical information will come from well-conducted pharmacokinetic studies just as was done previously by Sumner Yaffe and other pediatric investigators.…”

“…For example, earlier work by investigators associated with this supplement sought to define a method for separating the drug dispositional effects of pharmacogenetics from those related to pediatric ontogeny . Similarly, the effects of transporters in pediatric PBPK models have been addressed …”

Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

“…However, it should be emphasized that the availability of quality human pediatric tissues is scarce and does not allow for P-gp investigations with larger sample sizes and bettercontrolled conditions (9). Despite all the above-mentioned limitations, Lam's study is cited by many review articles stating that human brain P-gp is fully mature at 3-6 months of age (7,(35)(36)(37)(38)(39).…”

Role of Transporters in Drug Development

“…Rodieux et al discuss the causes and consequences of variability in drug transporter activity in the treatment of pediatric patients. 31 Through an extensive review of literature, the authors describe the impact and interdependence of various factors such as developmental differences, genetic factors, and comorbidities that may influence drug transporter activity. Further, the authors underscore the utility of PBPK approaches in integrating drug-and patient-specific parameters, including drug transporter ontogeny, to further improve the predictions of pharmacokinetics in pediatric patients.…”

“…Rodieux et al discuss the causes and consequences of variability in drug transporter activity in the treatment of pediatric patients . Through an extensive review of literature, the authors describe the impact and interdependence of various factors such as developmental differences, genetic factors, and comorbidities that may influence drug transporter activity.…”