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

Suresh K. Agarwal, Ahmed Hamed Salem, Alexey Danilov, Beibei Hu, Soham Puvvada, Martin Gutierrez, David Chien, Lionel D. Lewis, Shekman L. Wong

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36 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)846-854
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Issue number4
Publication statusPublished - 2017



  • BCL-2
  • drug–drug interaction
  • ketoconazole
  • pharmacokinetics
  • venetoclax

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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