Abstract 755: A randomized, open-label, phase 1 study to evaluate the effect of food on tivantinib (ARQ 197) pharmacokinetics

Abstract

Abstract Background: Tivantinib (ARQ 197) is a selective inhibitor of c-MET that is administered orally. Therefore, the bioavailability of tivantinib may be affected by changes in gastric pH or emptying and gastrointestinal motility that occur in the presence of food. This study evaluated the effect of food on tivantinib pharmacokinetics (PK) to provide guidance regarding intake of meals in conjunction with tivantinib dosing in future clinical studies, and estimated the intra-subject variability of tivantinib when administered in fasting and fed conditions. Methods: Young healthy adults 18-45 years of age were eligible for the study. Subjects were randomized to 1 of 2 sequences. In sequence 1, subjects received a single dose of tivantinib (360 mg) in fasting conditions in Period 1 and in fed conditions in Periods 2 and 3. In sequence 2, subjects received a single dose of tivantinib (360 mg) in fed conditions in Period 1 and in fasting conditions in Periods 2 and 3. Each period was separated by ≤ 4 days, during which serial blood samples were collected for tivantinib analysis. PK parameters, including area under the curve (AUC), maximum concentration (Cmax), time to peak concentration (tmax), and terminal half-life (t1/2), were calculated and compared. Results: A total of 20 subjects (19 male and 1 female) were randomized. Under fed conditions, total exposure of tivantinib was significantly higher (approximately 2.7-times for AUC and 3.6-times for Cmax) compared with fasting conditions (ratios of geometric least-square means and 90% confidence intervals were outside the 80%-125% bioequivalence interval). Time to maximum concentration (tmax) was prolonged when tivantinib was administered in fed conditions versus fasting conditions (4.0 vs 2.5 hours). Although t1/2 was longer in fasting versus fed conditions (19.0 vs 4.0 hours), nonparametric statistical analysis demonstrated that this difference was not statistically significant. Intra-subject variability was roughly 2-fold lower in fed conditions compared with fasting conditions. Five adverse events were reported in 2 subjects (10%), all of which were considered unrelated to study treatment. One subject withdrew consent and discontinued from the study for reasons unrelated to treatment. Conclusions: Administration of tivantinib in fed conditions results in relatively higher exposure with lower variability compared with fasting conditions. This may be explained by increased tivantinib solubility and more consistent absorption in the fed state. Based on this observation, tivantinib is currently recommended to be administered with meals in ongoing clinical studies, including the ongoing phase 3 study (MARQUEE™) in patients with nonsquamous non-small cell lung cancer. 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 755. doi:1538-7445.AM2012-755