title: Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies.
abstract: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses.
  
  
  
  Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-tand Cmaxfell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmaxin the presence of rifampin compared with olaparib alone).
  
  
  
  In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmaxtreatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmaxtreatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile.
  
  
  
  Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).
authors.affiliation: Medical Oncology, Sint-Augustinus-University of Antwerp, Antwerp, Belgium. Electronic address: luc.dirix@telenet.be.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.affiliation: Department of Medical Oncology, VU Medisch Centrum, Amsterdam, the Netherlands.
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Department of Medical Oncology, Ghent University Hospital and Heymans Institute of Pharmacology, Ghent, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rottey
authors.affiliation: Universitair Ziekenhuizen Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.affiliation: CHU Sart-Tilman and Liege University, Liege, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: Oncology Department, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Nielsen
authors.affiliation: The Royal Marsden and Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.affiliation: University College London Cancer Institute, London, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: Division of Medical Oncology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Judith de
authors.initials: J
authors.lastname: Vos-Geelen
authors.affiliation: Department of Oncology, University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Mau-Sørensen
authors.affiliation: Division of Medical Oncology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Patricia
authors.initials: P
authors.lastname: Soetekouw
authors.affiliation: Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: van Herpen
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: So
authors.affiliation: PHASTAR, London, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bannister
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010793:Phthalazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D010793:Phthalazines; D010879:Piperazines; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin; C531550:olaparib
keywords: CYP3A4; itraconazole; olaparib; pharmacokinetic; rifampin