Effect of Low- and High-Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First-in-Class BCL-2 Inhibitor

• Published in: Journal of clinical pharmacology Vol. 56; no. 11; p. 1355
• Main Authors: Salem, Ahmed Hamed, Agarwal, Suresh K, Dunbar, Martin, Nuthalapati, Silpa, Chien, David, Freise, Kevin J, Wong, Shekman L
• Format: Journal Article
• Language: English
• Published: England 01.11.2016
• Subjects: Adult; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic - blood; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Cross-Over Studies; Diet, Fat-Restricted - methods; Diet, High-Fat - methods; Dietary Fats - blood; Female; Food-Drug Interactions - physiology; Humans; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - blood; Sulfonamides - pharmacokinetics; BCL-2; CLL; NHL; food effect; bioavailability; fat; pharmacokinetics; venetoclax
• DOI: 10.1002/jcph.741

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions, in each of 2 periods; one period used the uncoated tablet, and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100-mg tablet under fasting conditions, after a low-fat breakfast or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median T of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, C and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased C and AUC by approximately 50% relative to low-fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.