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

Abstract

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.

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

“…Hence, the food effect on AUC determined in this study following a high‐fat (week 1 day –7) or low‐fat meal (week 6/7 day 1) relative to dose‐normalized AUC ∞ after a single dose under fasting conditions (week 1 day 1) may have been overestimated. However, these results were confirmed by the findings from a dedicated food‐effect study in healthy volunteers in whom venetoclax exposures increased by approximately 3.4‐ and 5.2‐fold after a low‐fat or high‐fat meal, respectively, compared to fasting conditions …”

Effectiveness of Venetoсlax in the Treatment of Chronic Lymphocytic Leukemia (Literature Review)

“…Пиковаяконцентрациявенетоклаксавкровидо-стигаетсячерез6-8чпослеприема.Времяполувыве-дения препарата после однократного приема 50мг составляет от 19 до 26 ч. Для достижения целевых фармакокинетических параметров препарат следует приниматьседой(илисразупосленее),посколькупи-щевыежирынеобходимыдляегопоступлениявкишеч-нуюлимфатическуюсистему [11].Отслеживатьиогра-ничиватьсодержаниежироввпищенетребуется [12].…”

Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia

“…C max and AUC are also increased 3-to 5-fold when taken with food, especially a highfat meal (45). The favored explanation for the food effect is that lipids in food increase venetoclax intestinal lymphatic transport.…”

“…Consequently, it is recommended that venetoclax be administered once daily with a meal. No special dietary adjustment is thought necessary (45). At steady state, the peak concentration of venetoclax at the recommended dose of 400 mg/day is 2.1 AE 1.1 mg/mL when taken with a low-fat meal (42,43).…”