Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics
Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics
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DOI：
10.3389/fphar.2019.01672
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发表时间：
2020-01-30
影响因子：
5.6
通讯作者：
McLachlan, Andrew J.
中科院分区：
文献类型：
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作者：
Adiwidjaja, Jeffry;Boddy, Alan V.;McLachlan, Andrew J.
长期使用伊马替尼对慢性粒细胞白血病（CML）儿童有效且耐受性良好，但确定伊马替尼在年轻患者中的最佳给药方案是一项挑战。伊马替尼和联合用药在这个“特殊”人群中的潜在相互作用也在很大程度上尚未探索。本研究采用基于生理学的药代动力学（PBPK）建模方法来研究儿科人群中最佳给药方案以及与伊马替尼的潜在药物相互作用。使用计算机模拟、体外药物代谢和体内药代动力学数据，在Simcyp模拟器（版本17）中开发了伊马替尼的PBPK模型，并使用一组独立的已发表临床药代动力学数据进行了验证。然后通过纳入器官大小的发育变化以及负责伊马替尼处置的药物代谢酶和血浆蛋白的成熟，将该模型外推至儿童和青少年（2-18岁）。PBPK模型描述了伊马替尼在成人和儿童人群中的药代动力学，并预测了与卡马西平（细胞色素P450（CYP）3A 4和2C 8诱导剂）的药物相互作用，具有良好的准确性（通过目视检查模拟结果和预测的药代动力学参数进行评价，这些参数在临床观察值的1.25倍范围内）。PBPK模拟表明，儿科伊马替尼的最佳给药方案范围为230-340 mg/m（2）/d，这得到了治疗儿童CML的推荐初始剂量的支持。模拟还强调，接受伊马替尼治疗的儿童和成人对药物调节具有相似的脆弱性。成功开发了伊马替尼的PBPK模型，该模型在预测伊马替尼在各年龄组的药代动力学方面表现出色。该PBPK模型有助于指导伊马替尼的最佳给药方案，并预测儿科人群中与伊马替尼调节剂的药物相互作用。
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.