Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- And Multiple-Dose Study

J Clin Pharmacol. 2016 Nov;56(11):1335-1343. doi: 10.1002/jcph.730.

Abstract

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUC by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.

Keywords: ABT-199/GDC-0199; BCL-2; CYP3A4; OATP; P-glycoprotein; interaction; pharmacokinetics; rifampin; venetoclax.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Adolescent
  • Adult
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / blood*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inducers / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions / physiology
  • Female
  • Humans
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Rifampin / administration & dosage*
  • Sulfonamides / administration & dosage
  • Sulfonamides / blood*
  • Sulfonamides / pharmacokinetics
  • Young Adult

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cytochrome P-450 CYP3A Inducers
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • venetoclax
  • Rifampin