title: Effects of patupilone on the pharmacokinetics and pharmacodynamics of warfarin in patients with advanced malignancies: a phase I clinical trial.
abstract: 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.
authors.affiliation: Corresponding Author: Apostolia M. Tsimberidou, The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA. atsimber@mdanderson.org
authors.forename: Apostolia-Maria
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Chris H M
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
authors.forename: Cynthia
authors.initials: C
authors.lastname: Uehara
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Alain
authors.initials: A
authors.lastname: Mita
authors.forename: Patrick
authors.initials: P
authors.lastname: Urban
authors.forename: Eugene
authors.initials: E
authors.lastname: Tan
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Vining
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D014859:Warfarin; C093788:epothilone B