title: Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma.
abstract: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax.
  
  
  
  Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8.
  
  
  
  Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC∞) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively.
  
  
  
  Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.|Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Ahmed Hamed
authors.identifier: 0000-0002-9261-1583
authors.initials: AH
authors.lastname: Salem
authors.affiliation: Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Hu
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona, USA.
authors.forename: Soham
authors.initials: S
authors.lastname: Puvvada
authors.affiliation: The Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.affiliation: Oncology Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chien
authors.affiliation: Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065692:Cytochrome P-450 CYP3A Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax; D007654:Ketoconazole
keywords: BCL-2; drug-drug interaction; ketoconazole; pharmacokinetics; venetoclax