Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours

Aims: This phase 1, open-label, crossover study sought to evaluate drug–drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein. Methods: The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily. Results: The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration–time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89–1.05) for caffeine, 0.88 (0.76–1.02) for S-warfarin, 0.89 (0.60–1.31) for omeprazole, 0.83 (0.67–1.02) for midazolam, and 0.69 (0.51–0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60–0.95). Conclusions: The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib.