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

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

Author information

1
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.
2
Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
3
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.
4
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
5
The University of Arizona Cancer Center, Tucson, Arizona, USA.
6
The Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, USA.
7
Oncology Development, AbbVie Inc., North Chicago, Illinois, USA.

Abstract

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

PMID:
27859472
PMCID:
PMC5346863
DOI:
10.1111/bcp.13175
[Indexed for MEDLINE]
Free PMC Article

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