Abstract 760: A randomized, crossover, phase 1 study to evaluate the effect of a strong CYP3A4 inhibitor on tivantinib (ARQ 197) pharmacokinetics in healthy subjects
Authors: Zahir Hamim , Oguma Toshihiro , Weiss Daniel , Walker Joseph , Tokui Taro 
Published: August 2012

Abstract
Background: Tivantinib is a selective, oral, non-ATP-competitive, small-molecule inhibitor of c-MET. In vitro data suggest that CYP2C19 and CYP3A4 are the major enzymes involved in tivantinib metabolism. Therefore, there is potential that CYP3A4 inhibitors may affect tivantinib pharmacokinetics (PK) leading to increased exposure. During the course of their disease, cancer patients receive multiple drugs, some of which may be strong CYP3A4 inhibitors. This open-label, 2-stage study evaluated the effect of ketoconazole, a strong inhibitor of CYP3A4, on tivantinib metabolism in adults with different CYP2C19 activity. Methods: Healthy adults (age 18 to 45 years) with no clinical conditions were eligible. In stage 1, healthy subjects who were either an extensive metabolizer (EM) or intermediate metabolizer (IM) based on CYP2C19 activity were randomized to 1 of 2 sequences, each consisting of two 8-day treatment periods under fed conditions with a 14-day washout between periods. In sequence 1, tivantinib (120 mg) was administered alone on day 4 of period 1 followed by ketoconazole (400 mg/day) with concomitant tivantinib (120 mg) on day 4 of period 2. The treatments were reversed in sequence 2. If there was no interaction, poor metabolizer (PM) subjects were to be analyzed in stage 2. Serial blood samples were collected for 96 hours after tivantinib administration, and area under the curve (AUC), maximum concentration (Cmax), and time to peak concentration (tmax) were calculated and statistically compared. Results: Sixteen subjects were randomized equally to 1 of 2 treatment sequences. When tivantinib was combined with ketoconazole, total exposure to tivantinib (AUC) was increased 2.1-fold and Cmax was increased 1.4-fold compared with tivantinib alone. Median tmax was similar for ketoconazole + tivantinib and tivantinib alone (4.75 vs 4.50 hours, respectively). Exposure to tivantinib was 2- to 3-fold higher in CYP2C19 IM subjects compared with CYP2C19 EM subjects, with or without ketoconazole. The median tmax for tivantinib was comparable for IM and EM subjects with or without ketoconazole (tivantinib, 4.50 vs 4.49 hours, respectively and ketoconazole + tivantinib, 5.00 vs 4.50 hours, respectively). A total of 10 adverse events (AEs) were reported in 5 subjects (31%); 4 AEs were considered related to ketoconazole and the remaining AEs were unrelated to study treatment. Two subjects discontinued the study because of elevated creatinine (related to ketoconazole) and elevated neutrophils (unrelated to treatment), respectively. Stage 2 assessment in CYP2C19 PM subjects was not performed. Conclusions: Concurrent administration of ketoconazole substantially increased tivantinib exposure. Therefore, caution should be exercised when strong CYP3A4 inhibitors are coadministered with tivantinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 760. doi:1538-7445.AM2012-760