Abstract C85: Drug interaction study of tivantinib in cancer subjects using a cocktail approach.
Authors: Tachibana Masaya , Papadopoulos Kyriakos P. , Strickler John , Puzanov Igor , Gajee Roohi , Wang Yibin , Zahir Hamim 
Published: August 2014

Abstract
Background: Tivantinib (ARQ197) is an orally administered cMET inhibitor currently under development as a cancer therapy. Nonclinical studies have indicated that tivantinib and its major metabolites have the potential to inhibit cytochrome P450 (CYP) 3A4, 2C19, 2C9, and 1A, and the P-glycoprotein (P-gp) at the clinical concentrations being studied in phase 3 studies. The objective of this drug interaction study was to assess the effect of tivantinib at steady state levels on the pharmacokinetics of CYP- and P-gp-specific probe drugs (modified Cooperstown 5 + 1 Cocktail) after multiple BID doses of tivantinib.
Methods: This was a phase 1, open-label, single-sequence, crossover study (NCT01517399) in subjects with advanced solid tumors. Each subject was administered five probe drugs in the absence or presence of tivantinib (360 mg BID): midazolam (CYP3A4), omeprazole (CYP2C19), S-warfarin (CYP2C9), caffeine (CYP1A), and digoxin (P-gp). Serial blood samples were collected to determine the pharmacokinetics of the probe drugs. Pharmacokinetic parameters were computed using a non-compartmental approach. Log-transformed pharmacokinetic parameters were analyzed using a linear mixed-effects model with treatment as fixed effects and subject as a random effect, and the ratio of geometric least-square (LS) means and the 90% CI for test treatment (Probe drug administered with tivantinib) to reference treatment (probe drug administered alone) were calculated. No drug interaction was concluded if the 90% CI of the LS mean ratios are within the range of 0.8-1.25.
Results: Twenty eight cancer subjects were enrolled. The ratios of geometric LS mean (90% CI) for total exposure parameter (AUClast) were as follows: midazolam, 0.83 (0.67, 1.02); omeprazole, 0.89 (0.60, 1.31); S[[Unable to Display Character: &#8209;]]warfarin, 0.88 (0.76, 1.02); caffeine, 0.97 (0.89, 1.05); and digoxin, 0.69 (0.51, 0.94). Small changes in exposure were observed for midazolam, omeprazole, and warfarin with AUClast decreased ∼17%. Consistent with decrease in omeprazole AUClast (∼11.1%), the mean omeprazole/5-hydroxyomeprazole AUC ratio decreased by 12.8%. For digoxin, mean AUClast decreased by 30.9%. No interaction was determined on the caffeine pharmacokinetics. The effect on peak exposures (Cmax) was similar to the effect on AUClast. Treatment with tivantinib in combination with probe drugs omeprazole/warfarin/caffeine/midazolam or digoxin was generally well tolerated.
Conclusion: These results suggested that coadministration of tivantinib 360 mg BID has a small or no effect on the pharmacokinetics of probe drugs used in this study. It is likely that the observed effect of tivantinib on CYP1A2, CYP2C9, CYP2C19, CYP3A4 and P-gp is of minimal clinical significance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C85.
Citation Format: Masaya Tachibana, Kyriakos P. Papadopoulos, John Strickler, Igor Puzanov, Roohi Gajee, Yibin Wang, Hamim Zahir. Drug interaction study of tivantinib in cancer subjects using a cocktail approach. [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 C85.