Interaction between crizotinib and tropifexor through in vitro and in vivo studies

TL;DR

This study investigates how the drug tropifexor affects the metabolism of crizotinib in both lab and animal models, showing potential drug interactions.

Contribution

A new UPLC-MS/MS method was developed to quantify crizotinib and its metabolite, and the inhibitory mechanisms of tropifexor on crizotinib metabolism were elucidated.

Findings

Tropifexor inhibits crizotinib metabolism via non-competitive and uncompetitive mechanisms in rat liver microsomes.

In vivo, tropifexor increased crizotinib's AUC and Cmax while decreasing its clearance in rats.

Tropifexor also reduced the clearance of the metabolite 2-Keto crizotinib.

Abstract

In the context of cancer treatment, the employment of multiple drug therapies frequently results in a high prevalence of drug-drug interaction (DDI) in clinical practice. Crizotinib is a tyrosine kinase inhibitor (TKI) used to treat non-small cell lung cancer (NSCLC). Tropifexor is a Farnesoid X Receptor (FXR) agonist used to treat non-alcoholic steatohepatitis (NASH) and other metabolic disorders. This study developed an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitative determination of crizotinib and 2-Keto crizotinib concentrations and investigated the effect of tropifexor on crizotinib metabolism. Results showed good linearity for crizotinib and 2-Keto crizotinib in plasma, with the method meeting all quantitative analysis requirements, including selectivity, accuracy, precision, stability, matrix effects, and recovery. In rat liver microsomes (RLM), tropifexor inhibited the metabolism of crizotinib via non-competitive and uncompetitive mechanisms, whereas in human liver microsomes (HLM), the inhibition occured through competitive and non-competitive mechanisms. In vivo studies in rats demonstrated that tropifexor significantly increased the AUC0−t, AUC0−∞, and Cmax of crizotinib by 35.7%, 36.9%, and 37.5%, respectively, and decreased the CLz/F of crizotinib by 25.2%. For the metabolite 2-Keto crizotinib, tropifexor reduced its CLz/F by 27.9%. Our study developed this UPLC-MS/MS method for the accurate and sensitive quantitative determination of crizotinib and 2-Keto crizotinib concentrations, and elucidated the inhibitory effect of tropifexor on crizotinib metabolism and its inhibitory mechanism. The results of this study will support the necessity of monitoring crizotinib plasma concentrations when used in combination therapy.

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