Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma

Br J Clin Pharmacol. 2017 Apr;83(4):846-854. doi: 10.1111/bcp.13175. Epub 2017 Jan 18.


Aims: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: BCL-2; drug-drug interaction; ketoconazole; pharmacokinetics; venetoclax.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Area Under Curve
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics*
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology*
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / pharmacology*
  • Lymphoma, Non-Hodgkin / drug therapy
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics*


  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cytochrome P-450 CYP3A Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • venetoclax
  • Ketoconazole