Effect of Ketoconazole, a Strong CYP3A Inhibitor, on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor, in Patients with Non-Hodgkin Lymphoma

Effect of Ketoconazole, a Strong CYP3A Inhibitor, on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor, in Patients with Non-Hodgkin Lymphoma:

Aim

To examine the effect of a strong CYP3A 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 through 11. Blood samples were collected predose and up to 96 hours 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 (C_max) 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 leukemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong inhibitors or inducers of CYP3A/P-gp is recommended.

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