Inhibition of acalabrutinib metabolism by finerenone and its molecular docking studies.

Abstract

Acalabrutinib is a frontline agent for chronic lymphocytic leukemia (CLL). The objective of this experiment was to screen 21 cardiovascular drugs with a focus on elucidating the metabolic inhibition of acalabrutinib by finerenone in vitro and in vivo. The ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to quantify acalabrutinib and its major active metabolite ACP-5862 in liver microsomes in vitro and in rats in vivo. The half-maximal inhibitory concentrations (IC₅₀) of finerenone in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 (rCYP3A4) were 7.00, 21.29 and 3.52 μM, respectively. In RLM and rCYP3A4, finerenone inhibited the metabolism of acalabrutinib via mixed-type inhibition (competitive and non-competitive), with a non-competitive inhibition observed in HLM. Compared with the control group, in vivo pharmacokinetic analysis indicated that finerenone co-administration increased acalabrutinib exposure, as reflected by 4.08-, 7.16-, and 3.96-fold increases in AUC_(0-t), AUC_(0-∞), and half-life (t_1/2), respectively, accompanied by an 86.02% reduction in the clearance (CL_z/F). Its metabolite ACP-5862 demonstrated a 57.47% and 65.12% decrease in AUC_(0-t) and the maximum concentration (C_max), respectively, while CL_z/F was increased by 0.79-fold. Finally, acalabrutinib and finerenone were evaluated for binding to cytochrome P450 3A4 (CYP3A4) by molecular docking, yielding binding energies of -2.36 and -2.19 kcal/mol, respectively. Thus, in vivo and in vitro results consistently indicated that finerenone inhibited the metabolism of acalabrutinib, providing the basis for individualized dosing considerations.