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

Published

Journal Article

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.

Full Text

Cited Authors

  • Tachibana, M; Papadopoulos, KP; Strickler, JH; Puzanov, I; Gajee, R; Wang, Y; Zahir, H

Published Date

  • January 2018

Published In

Volume / Issue

  • 84 / 1

Start / End Page

  • 112 - 121

PubMed ID

  • 28865153

Pubmed Central ID

  • 28865153

Electronic International Standard Serial Number (EISSN)

  • 1365-2125

International Standard Serial Number (ISSN)

  • 0306-5251

Digital Object Identifier (DOI)

  • 10.1111/bcp.13424

Language

  • eng