Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations

Abstract

There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics.The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P-PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P-PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P-PBPK modeling increased 33-fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P-PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug-drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P-PBPK models.

Physiologically Based Pharmacokinetic (PBPK) Model-Informed Dosing Guidelines for Pediatric Clinical Care: A Pragmatic Approach for a Special Population

“…Pediatric PBPK modeling matures rapidly. In 2020, the number of scientific publications on pediatric PBPK modeling was 34 compared to one publication in 2005 [ 28 ]. Yet, many more physiology and compound models are available in repositories.…”

Addressing drug safety of maternal therapy during breastfeeding using physiologically‐based pharmacokinetic modeling

“…When clinical lactation data are available, some of the uncertainty associated with extrapolation of the infant daily dose is removed. Here, we present two case studies where observed milk concentrations were available and the extrapolated infant daily dose was used to simulate plasma concentration time profiles in infants using a pediatric PBPK model (Johnson et al 2 ); one involves a drug–drug interaction for a combination therapy, and the other, the complex interplay between mother/infant and the impact of their respective CYP2B6 genotypes.…”

“…Although knowledge gaps remain, ongoing research relating to these processes in children, has allowed refinement of relevant physiological parameters and integration of more complex models. Thus, PBPK models which are increasingly used in pediatric clinical pharmacology, including drug development, are reaching maturation for applications with high regulatory impact 2 . In this paper, we discuss how “off the shelf” PBPK models for commonly used drugs, already robustly verified in terms of their disposition, can be used to assess safety concerns in breastfeeding infants as a consequence of the nursing mothers taking medication(s).…”

“…PBPK models which account for the complex interplay between physiological parameters and drug‐related characteristics, represent a mechanistic approach to predict the pharmacokinetics (PKs) of drugs in different populations, including nursing mothers 1 and infants. 2 Pediatric PBPK models account for the development of organs, including the ontogeny of specific enzymes and transporters involved in the disposition of a specific drug. Although knowledge gaps remain, ongoing research relating to these processes in children, has allowed refinement of relevant physiological parameters and integration of more complex models.…”

“…Thus, PBPK models which are increasingly used in pediatric clinical pharmacology, including drug development, are reaching maturation for applications with high regulatory impact. 2 In this paper, we discuss how “off the shelf” PBPK models for commonly used drugs, already robustly verified in terms of their disposition, can be used to assess safety concerns in breastfeeding infants as a consequence of the nursing mothers taking medication(s). Complex case studies will be used to demonstrate the validity of the approach.…”