title: Effect of co-administration of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics, safety and tolerability of navitoclax, a first-in-class oral Bcl-2 family inhibitor, in cancer patients.
abstract: OBJECTIVE
  Navitoclax is a targeted B-cell lymphoma-2 (Bcl-2) family protein inhibitor. The present study evaluated the effect of ketoconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetics of navitoclax in patients with cancer.
  
  
  METHODS
  Eleven patients with cancer were enrolled in this Phase I study. Single doses of navitoclax at 60 mg were administered orally on days 1 and 8. Ketoconazole at 400 mg was given once daily from days 7 through 10. Blood samples were collected pre-dose through 72 h after each navitoclax dose.
  
  
  RESULTS
  Ten patients had evaluable pharmacokinetic data and were, therefore, included in pharmacokinetic statistical analyses. The maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinite time (AUC∞) of navitoclax in the presence of ketoconazole was 94% (90% confidence interval (CI)=53165%) and 155% (90% CI=91264%), respectively of those observed with navitoclax when administered alone. The increase in navitoclax AUC∞ was primarily driven by two patients, who had 5-fold and 11-fold increases, respectively, in navitoclax AUC∞ in the presence of ketoconazole. These two participants had unusually low plasma drug exposure when navitoclax was administered alone, and their navitoclax exposure in the presence of ketoconazole increased to be within the range of the other 8 patients. There were no adverse events related to navitoclax exposure reported in these 2 patients.
  
  
  CONCLUSIONS
  Co-administration of navitoclax with ketoconazole did not increase navitoclax exposure above that observed with navitoclax monotherapy and did not appear to affect its safety profile. Results suggest CYP3A does not play a major role in elimination of navitoclax.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064-1802, U.S.A. sale0074@umm.edu.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
authors.forename: Jianning
authors.initials: J
authors.lastname: Yang
authors.forename: Alison
authors.initials: A
authors.lastname: Graham
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D012307:Risk Factors; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D007654:Ketoconazole; C528561:navitoclax
keywords: Bcl-2; Navitoclax; cancer; cytochrome P450 3A; drug interaction; ketoconazole