Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

Abstract

Long-term use of imatinib is effective and well-tolerated in children with chronic myeloid leukaemia (CML) yet defining an optimal dosing regimen for imatinib in younger patients is a challenge. The potential interactions between imatinib and coadministered drugs in this "special" population also remains largely unexplored. This study implements a physiologically based pharmacokinetic (PBPK) modeling approach to investigate optimal dosing regimens and potential drug interactions with imatinib in the paediatric population. A PBPK model for imatinib was developed in the Simcyp Simulator (version 17) utilizing in silico, in vitro drug metabolism, and in vivo pharmacokinetic data and verified using an independent set of published clinical pharmacokinetic data. The model was then extrapolated to children and adolescents (aged 2-18 years) by incorporating developmental changes in organ size and maturation of drug-metabolising enzymes and plasma protein responsible for imatinib disposition. The PBPK model described imatinib pharmacokinetics in adult and paediatric populations and predicted drug interaction with carbamazepine, a cytochrome P450 (CYP)3A4 and 2C8 inducer, with a good accuracy (evaluated by visual inspections of the simulation results and predicted pharmacokinetic parameters that were within 1.25-fold of the clinically observed values). The PBPK simulation suggests that the optimal dosing regimen range for imatinib is 230-340 mg/m 2 /d in paediatrics, which is supported by the recommended initial dose for treatment of childhood CML. The simulations also highlighted that children and adults being treated with imatinib have similar vulnerability to CYP modulations. A PBPK model for imatinib was successfully developed with an excellent performance in predicting imatinib pharmacokinetics across age groups. This PBPK model is beneficial to guide optimal dosing regimens for imatinib and predict drug interactions with CYP modulators in the paediatric population.

Impact of Hepatic CYP3A4 Ontogeny Functions on Drug–Drug Interaction Risk in Pediatric Physiologically‐Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study

“…43 In the case of imatinib PBPK model (children > 2 years old), no significant differences were observed. 44 However, no studies reported systematic comparisons of these hepatic CYP3A4 ontogeny functions for the evaluation of DDI risk in children.…”

Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach

“…As carbamazepine plays a crucial role in the treatment of epilepsy (recommended as first line treatment option by Cochrane [ 11 ] and included in the World Health Organization (WHO) Model List of Essential Medicines [ 12 ]), surveillance and examination of its DDI potential is important to ensure a safe drug therapy. The FDA recommends the use of carbamazepine as CYP3A4 and CYP2B6 inducer in clinical drug–drug interaction studies and it was applied in recent clinical trials, for example, with etonorgestrel, basimglurant or bitopertin [ 13 ]. In this case, the physiologically based pharmacokinetic (PBPK) modeling technique can come in as a helpful tool.…”

“…More than 60% of PBPK models submitted to the FDA investigate DDIs. Several published studies investigate the DDI potential of carbamazepine using a PBPK modeling approach [ 13 , 16 , 17 , 18 , 19 ]. While carbamazepine is typically used as an inducer to investigate the interaction with a substrate, our study aims to provide a comprehensive overview on the pharmacokinetics of carbamazepine and its DDIs, investigating carbamazepine not only as inducer but also as victim drug.…”

Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically‐based pharmacokinetic modelling approach

“…Input parameters for the PBPK model of imatinib and bosutinib 59 are summarised in Table S1. Development and verification of the PBPK model of imatinib in adults from European ancestry at both single‐dose administration and steady‐state have been detailed elsewhere 60 . The PBPK model was also verified against clinical pharmacokinetic data in people from Chinese ancestry (unpublished).…”