Feasibility of a Pragmatic PBPK Modeling Approach: Towards Model-Informed Dosing in Pediatric Clinical Care

Abstract

Background and Objective More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data are needed to support off-label dosing, however for many drugs such data are either sparse or not representative. Physiologicallybased pharmacokinetic (PBPK) models are increasingly used to study PK and guide dosing decisions. Building compound models to study PK requires expertise and is time-consuming. Therefore, in this paper, we studied the feasibility of predicting pediatric exposure by pragmatically combining existing compound models, developed e.g. for studies in adults, with a pediatric and preterm physiology model. Methods Seven drugs, with various PK characteristics, were selected (meropenem, ceftazidime, azithromycin, propofol, midazolam, lorazepam, and caffeine) as a proof of concept. Simcyp ® v20 was used to predict exposure in adults, children, and (pre)term neonates, by combining an existing compound model with relevant virtual physiology models. Predictive performance was evaluated by calculating the ratios of predicted-to-observed PK parameter values (0.5-to 2-fold acceptance range) and by visual predictive checks with prediction error values. Results Overall, model predicted PK in infants, children and adolescents capture clinical data. Confidence in PBPK model performance was therefore considered high. Predictive performance tends to decrease when predicting PK in the (pre)term neonatal population. Conclusion Pragmatic PBPK modeling in pediatrics, based on compound models verified with adult data, is feasible. A thorough understanding of the model assumptions and limitations is required, before model-informed doses can be recommended for clinical use.Rick Greupink and Saskia N. de Wildt: Joint last author.

Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care

“…Our study sides with recent critiques of the twofold criterion. van der Heijden et al [ 29 ] argued that more stringent ranges for predicted-to-observed ratios should be considered. Another limitation of the twofold ranges was highlighted by Guest et al [ 30 ] and Abduljalil et al [ 13 ] who demonstrated the necessity of incorporating variability of the PK data into the evaluation procedure.…”

Physiologically‐Based Pharmacokinetic Modeling for Drug Dosing in Pediatric Patients: A Tutorial for a Pragmatic Approach in Clinical Care

“…A less time-consuming PBPK modeling approach in which pre-existing compound models are combined with pediatric physiology models can be pragmatic and feasible to predict PK and guide drug dosing in pediatric clinical care. 12,13 Rapid growth of PBPK to support drug development decisions in the last decade resulted in active engagement of major regulators to develop guidelines around the use of this technology. The process is a work in progress.…”

“…We described a pragmatic workflow for pediatric PBPK model verification before, applying it to several drugs. 13 In this approach, a PBPK model is first verified with an adult population to demonstrate adequate predictive performance when predicting PKs in adults before integrating age-related physiological changes to predict PK in pediatrics and subsequently, if relevant, in preterm neonates. Below we describe relevant steps in more detail and we outline how the approach can be applied in three scenarios of decreasing clinical data availability for model verification.…”

“…Often, these models were developed to simulate PKs in adult populations, and were rarely explored for their potential to guide drug dosing in children. A less time‐consuming PBPK modeling approach in which pre‐existing compound models are combined with pediatric physiology models can be pragmatic and feasible to predict PK and guide drug dosing in pediatric clinical care 12,13 …”

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

“…However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. This approach relies on the established principles of mechanistic PBPK modelling to describe tissue volumes, tissue perfusion, renal/liver function, blood biochemistry and drug metabolism enzyme/and drug transporter protein expression [ 15 ], in addition to the inclusion of development changes [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”