Evaluation of Potential Effects of CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Fruquintinib in Healthy Subjects

Cytochrome P450 (CYP) 3A plays a significant role in fruquintinib metabolism in vitro. This 2-part, 2-period fixed-sequence study investigated the impact of CYP3A inhibition (itraconazole) and CYP3A induction (rifampin) on the pharmacokinetics (PK) of fruquintinib and M11, its main metabolite. Fourteen healthy subjects in each part received a single dose of fruquintinib 5 mg alone in Period 1 and with itraconazole (Part A) or rifampin (Part B) in Period 2 under fasted conditions. Itraconazole or rifampin was administered daily 4 or 7 days before coadministration, respectively; administration of both continued throughout the PK sampling period. PK samples were collected before dosing and over 168 hours after fruquintinib dosing. Coadministration with itraconazole resulted in an increase of fruquintinib systemic exposure, determined by area under the plasma concentration-time curves (AUCs) by approximately 10%. Decreases in M11 AUCs and maximum plasma concentration (C_max) ranged from 44% to 55% but were not considered clinically meaningful. Rifampin reduced fruquintinib C_max and AUCs by 12% and 65%, respectively. Rifampin had a marginal effect on M11 AUCs and increased M11 C_max by 2.3-fold. Data support that concomitant use of fruquintinib with potent CYP3A inducers of rifampin-like potency should be avoided, but no dose adjustment is recommended when coadministered with CYP3A inhibitors.