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Clinical Trial
. 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

Suresh K Agarwal  1 , Ahmed Hamed Salem  1   2 , Alexey V Danilov  3   4 , Beibei Hu  1 , Soham Puvvada  5 , Martin Gutierrez  6 , David Chien  7 , Lionel D Lewis  3 , Shekman L Wong  1
Affiliations
Clinical Trial

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 et al. Br J Clin Pharmacol. 2017 Apr.

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.

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Figures

Figure 1
Figure 1
Study design
Figure 2
Figure 2
Plasma venetoclax and M27 metabolite concentration (mean + SD) vs. time profiles following administration of 50 mg venetoclax alone on Day 1 and with 400 mg ketoconazole on Day 8 (n = 11)
Figure 3
Figure 3
Individual venetoclax C max and AUC∞ values after administration of 50 mg venetoclax alone on Day 1 and after coadministration with 400 mg ketoconazole on Day 8 (n = 11). *Red line denotes the subject who experienced thrombocytopenia and also took diltiazem, a moderate CYP3A inhibitor, throughout the study
Figure 4
Figure 4
Relationship between body weight and venetoclax AUC∞ on Day 1
See this image and copyright information in PMC

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