Abstract A5: Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants.

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Abstract Background: L is an orally administered multitargeted tyrosine kinase inhibitor of VEGF receptors 1, 2, 3; FGF receptors 1, 2, 3, 4; PDGFR-β; RET; and KIT under clinical investigation in solid tumors at doses of 24 mg/d. This study in volunteers assessed the influence of P-glycoprotein (Pgp) inhibition (single-dose R) and simultaneous CYP3A4 and Pgp induction (multiple-dose R) on L PK parameters. Methods: This was a single-center, single-dose, open-label, sequential, 3-period study. Subjects were administered 3 regimens with a 14-day washout between each treatment. Subjects received a single oral dose of L 24 mg on Day 1 (Period 1), Day 15 (Period 2), and Day 43 (Period 3). In Period 2 on Day 15, subjects received a single oral dose of rifampin 600 mg coadministered with L. In Period 3, subjects received oral rifampin 600 mg/d for 21 days (Days 29 to 49). Results: 15 subjects were enrolled and completed the study. Single-dose rifampin increased free (unbound) L AUC0-∞ (32%) and Cmax (30%). Multidose rifampin decreased free L AUC0-∞ (9%) without a corresponding decrease in Cmax; mean t1/2(free L) decreased by ∼2.5 h (to ∼17 h) following single-dose rifampin and by ∼5 h following multidose R. The 90% confidence intervals (CIs) of the geometric least squares (GLS) mean ratios for Cmax and AUCs were above the upper CI boundary of the prespecified bioequivalence interval of 80%-125% following a single rifampin dose but within the prespecified bioequivalence interval following multidose R. Headache (n=3, 20%) was the most frequently reported treatment-emergent adverse event (TEAE); 5 subjects reported mild or moderate treatment-related TEAEs (n=5, 33%) most frequently nausea (n=3, 20%) and diarrhea (n=2, 13%). Conclusions: L exposure was increased by single-dose rifampin but decreased by multiple rifampin doses. The magnitude of these changes was relatively small and likely not clinically meaningful. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A5. Citation Format: Robert Shumaker, Jagadeesh Aluri, Jean Fan, Gresel Martinez, Gary A. Thompson, Min Ren. Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A5.