Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

• Published in: Clinical pharmacology in drug development Vol. 7; no. 4; pp. 435 - 440
• Main Authors: Cheung, Tommy T., Salem, Ahmed Hamed, Menon, Rajeev M., Munasinghe, Wijith P., Bueno, Orlando F., Agarwal, Suresh K.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2018
• Subjects: ABT‐199; Adult; BCL‐2; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; China - ethnology; Chinese; Drug Dosage Calculations; Female; Half-Life; Healthy Volunteers; Humans; Male; Middle Aged; Pharmacokinetics; Pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; venetoclax; China; pharmacokinetics; BCL-2; Chinese; venetoclax; ABT-199
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.395

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult‐to‐treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first‐generation Han Chinese subjects received a single 100‐mg dose of venetoclax following a low‐fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax, AUCinf, and terminal half‐life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non‐Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure–response relationship of venetoclax in non‐Asian CLL subjects, a 400‐mg once‐daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open‐label study in Chinese subjects with R/R CLL.