Influence of CYP2D6, CYP3A, and ABCG2 Genetic Polymorphisms on Ibrutinib Disposition in Chinese Healthy Subjects

<b>Objectives</b>: This study aimed to elucidate the determinants of interindividual variability in the pharmacokinetics of ibrutinib among healthy Chinese subjects, focusing on the influence of demographic characteristics, dietary conditions, and genetic polymorphisms on CYP enzymes and ABC transporters. <b>Methods</b>: Thirty-two participants were randomly assigned to either a fasting (n = 16) or fed (n = 16) group, each receiving a single 140 mg oral dose of ibrutinib. Plasma concentrations were quantified using a validated UPLC-MS/MS method. Genetic polymorphisms in CYP3A4, CYP3A5, CYP2D6, and ABCG2 were identified by Sanger sequencing. Pharmacokinetic parameters, including apparent clearance (CL/F), maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t), and time to maximum concentration (Tmax), were estimated by non-compartmental analysis and statistically evaluated for associations with demographic, dietary, and genetic variables. <b>Results</b>: Food intake significantly affected ibrutinib pharmacokinetics, with postprandial administration resulting in reduced CL/F and increased Cmax and AUC0-t (<i>p</i> < 0.01). Gender differences were also observed, as females exhibited higher CL/F, lower Cmax, and AUC0-t than males (<i>p</i> < 0.05). The CYP2D6 c.100C>T polymorphism significantly decreased CL/F and increased exposure in fasting and male subjects (<i>p</i> < 0.05), but this effect was absent under fed conditions. Conversely, the ABCG2 c.421C>A variant was associated with increased CL/F and decreased AUC0-t (<i>p</i> < 0.05), while other genotypes exerted negligible effects. <b>Conclusions</b>: Ibrutinib pharmacokinetics are significantly modulated by dietary status, gender, and genetic polymorphisms, particularly CYP2D6 c.100C>T and ABCG2 c.421C>A. These findings underscore the importance of integrating pharmacogenetic and physiological factors into individualized dosing strategies to optimize therapeutic efficacy and minimize adverse effects.