Adiwidjaja Jeffry, Boddy Alan V, McLachlan Andrew J
Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia.
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
Front Pharmacol. 2020 Jan 30;10:1672. doi: 10.3389/fphar.2019.01672. eCollection 2019.
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 , drug metabolism, and 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/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.
长期使用伊马替尼对慢性粒细胞白血病（CML）患儿有效且耐受性良好，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。在这一“特殊”人群中，伊马替尼与同时服用的药物之间的潜在相互作用在很大程度上仍未得到探索。本研究采用基于生理的药代动力学（PBPK）建模方法，研究儿科人群中伊马替尼的最佳给药方案以及潜在的药物相互作用。利用药物代谢和药代动力学数据，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情况，将该模型外推至儿童和青少年（2至18岁）。该PBPK模型描述了成人和儿科人群中伊马替尼的药代动力学，并预测了与细胞色素P450（CYP）3A4和2C8诱导剂卡马西平的药物相互作用，预测准确性良好（通过直观检查模拟结果以及预测的药代动力学参数在临床观察值的1.25倍以内进行评估）。PBPK模拟表明，儿科患者中伊马替尼的最佳给药方案范围为230 - 340 mg/m²/d，这得到了儿童CML治疗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CYP调节的易感性相似。成功开发了伊马替尼的PBPK模型，在预测不同年龄组伊马替尼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，并预测儿科人群中伊马替尼与CYP调节剂的药物相互作用。
