Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy.

摘要: Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment non-small cell lung cancer. A full understanding its disposition and capacity for interaction with other medications will facilitate effective use as single agent combination therapy.Experimental Design: Recombinant cytochrome P450s liver microsomal preparations were to identify novel pathways osimertinib metabolism vitro panel knockout mouse lines humanized drug establish relevance these vivoResults: Although some metabolites similar human samples there several significant differences, particular marked species difference involved. The murine Cyp2d gene cluster played predominant role mouse, whereas CYP3A4 was major enzyme responsible metabolism. Induction this mice substantially decreased circulating exposure. Importantly, we discovered further pathway involving CPY1A1. Modulation CYP1A1/CYP1A2 levels markedly reduced parent concentrations, significantly altering metabolite pharmacokinetics (PK) vivoConclusions: We demonstrate that P450 expressed smokers' lungs tumors has metabolise osimertinib. This could be defining outcome treatment. work also illustrates how P450-humanized can mitigate differences thereby model vivo effect critical metabolic on anti-tumor response. Clin Cancer Res; 24(9); 2138-47. ©2018 AACR.