The pharmacokinetics of gefitinib in a Chinese Cancer population group: a virtual clinical trials population study

Gefitinib, a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is used to treat non-small-cell lung cancer (NSCLC). Lung cancer rates are high in China and are expected to increase over the next decade. CYP 2D6 intermediate metaboliser (IM) phenotypes are more prevalent in the Chinese population compared to Caucasians; the increased risk of drug-drug interactions (DDI) with chemotherapy polypharmacy may lead to different clinical pharmacokinetics outcomes for Chinese patients. This study developed and validated a virtual Chinese cancer population for the pragmatic assessment of gefitinib DDI as a victim drug in Chinese and Caucasian cancer populations. When assessing the impact of 2D6 phenotypes on bupropion mediated CYP 2D6 DDI in Chinese cancer population, we found that AUC increased by at least 60% in extensive metabolizers (EM) and 30% in IM. As a result, fmCYP2D6 was reduced by 15% in IM in the presence of bupropion, translating into > 70% of EM subjects and > 48% of IM subjects with trough concentrations at steady state (Ctrough,ss) below the gefitinib target trough level. The PBPK model predicted that a 500 mg once daily dose in both EM and IM subjects successfully reduced the percent of subjects below the Ctrough,ss. Such changes in Ctrough,ss warrant further investigation and highlight the ability of pharmacokinetic modelling to investigate populations that may be difficult to recruit for traditional clinical studies.