5 years ago

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

Hamim Zahir, Roohi Gajee, John H. Strickler, Yibin Wang, Kyriakos P. Papadopoulos, Igor Puzanov, Masaya Tachibana
Aim 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 (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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13424

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