Adiwidjaja Jeffry, Gross Annette S, Boddy Alan V, McLachlan Andrew J
Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, Indonesia.
Br J Clin Pharmacol. 2022 Feb;88(4):1735-1750. doi: 10.1111/bcp.15084. Epub 2021 Oct 15.
This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens.
A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (C ).
The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained C in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400-600 mg/d) to achieve the desirable range of C (1000-3200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600-800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups; however, the clinical data to support this are currently limited.
PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.
本研究采用基于生理学的药代动力学（PBPK）建模方法，研究伊马替尼药代动力学和给药方案的种族间差异。
在Simcyp模拟器（版本17）中建立伊马替尼的PBPK模型，整合体外药物代谢和临床药代动力学数据。该模型考虑了伊马替尼处置过程中涉及的药物代谢酶和蛋白质在体型和丰度方面的种族差异。在不同给药方案和种族群体中评估该模型预测伊马替尼药代动力学的效用。然后根据既定的谷浓度（C）范围评估种族对伊马替尼给药的影响。
伊马替尼的PBPK模型在描述药代动力学和不同种族患者达到的C方面表现出出色的预测性能，预测差异在已发表研究中临床报告值的1.25倍以内。PBPK模拟表明，欧洲、日本和中国血统人群使用相似剂量的伊马替尼（400 - 600mg/d）可达到理想的C范围（1000 - 3200ng/mL）。模拟表明，非洲血统患者可能受益于更高的初始剂量（600 - 800mg/d）以达到伊马替尼目标浓度，因为与其他种族相比，伊马替尼的表观清除率（CL/F）更高；然而，目前支持这一点的临床数据有限。
PBPK模拟突出了欧洲和非洲血统人群在伊马替尼推荐初始剂量方面的潜在种族差异，但中国和日本血统人群之间没有这种差异。
