Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.

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Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day1 of period 1 and day 3 of period 2. Subjects received azithromycin 500mg on day1 and 250mg once daily on days2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. AbbVie in collaboration with Genentech/Roche.