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

Jeffry Adiwidjaja,Andrew J Mclachlan,Alan V Boddy

doi:10.3389/fphar.2019.01672

Jeffry Adiwidjaja, Andrew J Mclachlan + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2019.01672

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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/m2/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.

Highlights

Imatinib has revolutionised the treatment for cancer and led to a subsequent discovery of a class of drugs known as small molecule kinase inhibitors (Rowland et al, 2017)
All simulated pharmacokinetic parameters fell within 1.25-fold of those reported in clinical pharmacokinetic studies (Table 2), except for peak concentrations of imatinib at steady-state (Css,max) in the study by Marangon et al (2009)
We developed a physiologically based pharmacokinetic (PBPK) model for imatinib in adult populations and extrapolated its use to paediatrics

Summary

Introduction

Imatinib has revolutionised the treatment for cancer and led to a subsequent discovery of a class of drugs known as small molecule kinase inhibitors (Rowland et al, 2017). It is approved as the first-line treatment for chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST) in adult patients and for CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in children and adolescents (Suttorp et al, 2018a). A clinically significant interaction between imatinib and carbamazepine, a CYP3A and CYP2C8 inducer, was described in a 12-year old CML patient with epilepsy (Taguchi et al, 2014).

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