Micronutrients

All Drugs and Chemicals

Central Nervous System Stimulants

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

Anti-Arrhythmia Agents

Cardiotonic Agents

Anticoagulants

Gastrointestinal Agents

Coagulants

Other Dietary Supplements

Vitamins

Caffeine

Midazolam

Digoxin

Warfarin

Omeprazole

Vitamin K

Trace Elements

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

Phosphodiesterase Inhibitors

Enzyme Inhibitors

Antacids

Anti-Ulcer Agents

Proton Pump Inhibitors

Protective Agents

Antifibrinolytic Agents

Hemostatics

Menadione

Menaquinone

Naphthoquinone

Phylloquinone

All drugs except vitamin K will be administered as a single dose once by itself as a reference treatment and once with tivantinib

three oral 120 mg tablets administered twice a day

tivantinib

One 40 mg oral capsule once alone and once again with tivantinib

omeprazole

One 10 mg oral tablet once alone and once again with tivantinib

s-warfarin

One 200 mg oral tablet once alone and once again with tivantinib

caffeine

One oral 5 mg tablet on multiple days when and around warfarin administration

vitamin K

One oral 0.25 mg tablet once alone and once again with tivantinib

digoxin

Intravenous 1.5 mg dose once alone and once again with tivantinib

midazolam

Hamim Zahir, BPharm, PhD

The purpose of this study is to determine the effects of tivantinib on the pharmacokinetics of omeprazole, s-warfarin, caffein, midazolam, or digoxin in patients with cancer.

Nonclinical studies have indicated that tivantinib (parent molecule) has the potential to inhibit CYP3A4 (\[I\]/Ki=0.15, midazolam as substrate), CYP2C19 (\[I\]/Ki=0.98), CYP2C9 (\[I\]/Ki=0.44), and CYP1A (\[I\]/Ki=0.37), and the efflux transporter P glycoprotein (P-gp) (I2/IC50=82) at the clinical concentrations being studied in the Phase 3 development program. In addition, tivantinib has major circulating plasma metabolite(s) which also have been shown in nonclinical studies to exhibit similar CYP inhibition potential. The results of this study will evaluate the potential of tivantinib to influence the pharmacokinetics of CYP3A4/CYP2C19/CYP2C9/CYP1A and/or P-gp substrates, and help to provide the guidance to clinicians on co-administration of tivantinib with drugs metabolized by CYP3A4/CYP2C19/CYP2C9/ CYP1A and/or transported by P-gp.

Drug-drug Interaction Study of Tivantinib (ARQ 197) With Omeprazole, S-warfarin, Caffeine, Midazolam, and Digoxin in Cancer Subjects

A Phase 1, Open-Label, Single-Sequence Crossover Study Assessing the Effect of Tivantinib (ARQ 197) on the Pharmacokinetics of Omeprazole/S-Warfarin/Caffeine/Midazolam and Digoxin in Cancer Subjects

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Parameters of S-warfarin/caffeine/midazolam and digoxin (area under the concentration-time curve from time 0 to the last quantifiable concentration \[AUC last\] and area under the curve from time of dosing extrapolated to infinity \[AUC 0-inf\]) when warfarin/caffeine/midazolam and digoxin are administered alone or in combination with tivantinib

The ratios of omeprazole exposures vs. 5-hydroxyomeprazole exposures in terms of AUC last and AUC 0-inf when omeprazole is administered alone or in combination with tivantinib.

Maximum observed concentration in plasma \[Cmax\] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

Maximum observed concentration in plasma \[Tmax\] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

Apparent oral clearance \[CL/F\] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

Apparent volume of distribution \[V/F\] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

Spots Global Cancer Trial Database for pk interaction in advanced solid tumors with our drug and other drugs