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

Publication ,  Journal Article
Agarwal, SK; Tong, B; Bueno, OF; Menon, RM; Salem, AH
Published in: Adv Ther
November 2018

INTRODUCTION: 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. METHODS: In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. RESULTS: 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. CONCLUSIONS: 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. FUNDING: AbbVie in collaboration with Genentech/Roche.

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Published In

Adv Ther

DOI

EISSN

1865-8652

Publication Date

November 2018

Volume

35

Issue

11

Start / End Page

2015 / 2023

Location

United States

Related Subject Headings

  • Sulfonamides
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Humans
  • Healthy Volunteers
  • General Clinical Medicine
  • Female
  • Drug Monitoring
  • Drug Interactions
  • Dose-Response Relationship, Drug
  • Cytochrome P-450 CYP3A
 

Citation

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Agarwal, S. K., Tong, B., Bueno, O. F., Menon, R. M., & Salem, A. H. (2018). Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Adv Ther, 35(11), 2015–2023. https://doi.org/10.1007/s12325-018-0793-y
Agarwal, Suresh K., Bo Tong, Orlando F. Bueno, Rajeev M. Menon, and Ahmed Hamed Salem. “Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.Adv Ther 35, no. 11 (November 2018): 2015–23. https://doi.org/10.1007/s12325-018-0793-y.
Agarwal, Suresh K., et al. “Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.Adv Ther, vol. 35, no. 11, Nov. 2018, pp. 2015–23. Pubmed, doi:10.1007/s12325-018-0793-y.
Agarwal SK, Tong B, Bueno OF, Menon RM, Salem AH. Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Adv Ther. 2018 Nov;35(11):2015–2023.
Journal cover image

Published In

Adv Ther

DOI

EISSN

1865-8652

Publication Date

November 2018

Volume

35

Issue

11

Start / End Page

2015 / 2023

Location

United States

Related Subject Headings

  • Sulfonamides
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Humans
  • Healthy Volunteers
  • General Clinical Medicine
  • Female
  • Drug Monitoring
  • Drug Interactions
  • Dose-Response Relationship, Drug
  • Cytochrome P-450 CYP3A