CYP3A4‐Mediated Metabolism and Drug–Drug Interaction Potential of Abemaciclib and Letrozole In Vitro

Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, is used in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Letrozole, a non-steroidal aromatase inhibitor, is also used in hormone-dependent breast cancer treatment, primarily in postmenopausal women, and can be prescribed in combination with abemaciclib. This study investigates the metabolic profile of abemaciclib and its interaction with letrozole, focusing on the enzymatic parameters and potential inhibitory and inductive effects when both drugs are administered simultaneously. The study utilized human liver microsomes (HLM) and recombinant cytochrome P450 3A4 enzyme (CYP3A4) systems to determine the metabolism rate and profile of abemaciclib. Abemaciclib metabolism in HLM resulted in the formation of N-desethylabemaciclib (M2) and hydroxyabemaciclib (M20) metabolites. Various concentrations of abemaciclib were incubated, and the formation of its metabolites was observed using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The Michaelis-Menten constants for the formation of M2 and M20 were 43.21 ± 9.88 and 67.67 ± 11.25 µM, with a higher reaction rate observed for M20. The study confirmed CYP3A4 as the primary enzyme metabolizing abemaciclib. The inhibitory and inductive effects of abemaciclib and letrozole on CYP3A4 were then examined through different incubation protocols. Letrozole demonstrated direct inhibition of CYP3A4, reducing the formation of abemaciclib's main metabolites. Additionally, abemaciclib metabolites further inhibited CYP3A4, showing a potential for pharmacokinetic interactions when the drugs are used together. This study highlights significant interactions between abemaciclib and letrozole, particularly their combined inhibitory effects on CYP3A4.