Dataset Information

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/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.

SUBMITTER: Adiwidjaja J

PROVIDER: S-EPMC7002565 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Adiwidjaja Jeffry J Boddy Alan V AV McLachlan Andrew J AJ

Frontiers in pharmacology 20200130

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 ...[more]

PMID: 32082165

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Project description:Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.

Dataset Information

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

Publications

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

Similar Datasets

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