Patupilone is a novel microtubule-targeting
cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of
warfarin when administered concomitantly with
patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center,
drug-drug interaction study. In the core phase of the study, treatment consisted of
warfarin 20 mg orally (days 1 and 29) and
patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from
patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of
warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of
warfarin were not affected by
patupilone coadministration. The most common adverse events were
diarrhea,
nausea,
vomiting,
abdominal pain,
anorexia,
dehydration,
asthenia, and
peripheral neuropathy. Five (29.4%) patients experienced grade 3 study
drug-related adverse events (
diarrhea, 17.6%; increased INR, 11.8%;
dehydration, 5.9%; and
neutropenia, 5.9%). One patient with
triple-negative breast cancer (
estrogen receptor,
progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in
tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of
warfarin were not affected by
patupilone coadministration, suggesting that
patupilone has no clinically relevant effect on
CYP2C9 metabolism.
Patupilone showed antitumor activity in
triple-negative breast cancer.