Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer. Cancer Chemother Pharmacol 2011 Dec;68(6):1507-16
Date
04/19/2011Pubmed ID
21499896DOI
10.1007/s00280-011-1635-7Scopus ID
2-s2.0-85027921054 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
PURPOSE: Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways.
METHODS: This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase).
RESULTS: Forty-six patients were treated. The areas under the concentration-time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C (max) of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C (max) and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed.
CONCLUSIONS: Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.
Author List
Tsimberidou AM, Lewis N, Reid T, Burris H, Urban P, Tan EY, Anand S, Uehara C, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antineoplastic Combined Chemotherapy ProtocolsArea Under Curve
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Drug Interactions
Epothilones
Female
Humans
Male
Midazolam
Middle Aged
Neoplasms
Omeprazole
