Impact of metabolic enzyme activity variability on dabrafenib disposition.

Abstract

Introduction: The systemic exposure of dabrafenib correlates with its adverse drug reactions. A thorough understanding of its pharmacokinetic profile is crucial for precise clinical application.

Methods: An optimized liver microsomal incubation system was established to screen for inhibitors of dabrafenib metabolism. Recombinant human CYP3A4 microsomes were prepared using a baculovirus-insect cell expression system. Analytes were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The in vivo relevance of the inhibitory effects was further validated in Sprague-Dawley rats.

Results: Loratadine was identified as the most potent inhibitor, with IC₅₀ values of 14.01 ± 2.82 μM in rat liver microsomes and 52.40 ± 4.63 μM in human liver microsomes. It suppressed over 90% of dabrafenib metabolism through mixed-type inhibition. In vivo, co-administration of loratadine significantly increased the systemic exposure of dabrafenib compared to administration of dabrafenib alone. Specifically, the half-life (T_1/2) and peak concentration (C_max) increased by 548.65% and 237.43%, respectively, while CLZ/F and VZ/F were markedly reduced. These effects were attributed to inhibition mediated by loratadine. Additionally, CYP3A4 genetic polymorphisms considerably influenced the pharmacokinetics of dabrafenib: the CYP3A4.28 variant exhibited higher intrinsic clearance than the wild-type CYP3A4.1, whereas CYP3A4.8 showed reduced clearance.

Discussion: Both loratadine-mediated drug-drug interactions and CYP3A4 genetic polymorphisms critically alter the metabolism of dabrafenib. Dosage adjustments are necessary when these factors are present concurrently.