Interaction study between HIV protease inhibitors and alectinib in rats based on an ultra-performance liquid chromatography tandem mass spectrometry method

Abstract

We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and m/z 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC_0-t of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.