title: 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.
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 Cmaxand AUC∞by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmaxand 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 Cmaxand 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.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, IL, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, IL, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Hu
authors.affiliation: Oncology Development, AbbVie Inc, North Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chien
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, IL, USA.
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, IL, USA. ahmed.salem@abbvie.com.|Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. ahmed.salem@abbvie.com.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012293:Rifampin / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065701:Cytochrome P-450 CYP3A Inducers; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C579720:venetoclax; D012293:Rifampin
keywords: ABT-199/GDC-0199; BCL-2; CYP3A4; OATP; P-glycoprotein; interaction; pharmacokinetics; rifampin; venetoclax