title: Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Phase 1 Program, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 455, Houston, TX 77030, USA. atsimber@mdanderson.org
authors.forename: Apostolia-Maria
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Nancy
authors.initials: N
authors.lastname: Lewis
authors.forename: Tony
authors.initials: T
authors.lastname: Reid
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.forename: Patrick
authors.initials: P
authors.lastname: Urban
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Tan
authors.forename: Suraj
authors.initials: S
authors.lastname: Anand
authors.forename: Cynthia
authors.initials: C
authors.lastname: Uehara
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D034261:Epothilones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009853:Omeprazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D034261:Epothilones; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D008874:Midazolam; C093788:epothilone B