title: Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.
abstract: Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Aksana K
authors.initials: AK
authors.lastname: Jones
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Freise
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Oncology Development, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, 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: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood*; D015331:Cohort Studies; D004041:Dietary Fats / Q000008:administration & dosage / Q000097:blood; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004041:Dietary Fats; D013449:Sulfonamides; C579720:venetoclax
keywords: CYP3A interactions; food effect; population pharmacokinetics; renal and hepatic impairment; rituximab; venetoclax