Model-Informed Dosing of Venetoclax in Healthy Subjects: An Exposure-Response Analysis.

ABSTRACT

Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B-lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high-fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B-lymphocyte data to determine the exposure-response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B-lymphocyte levels by 24% (15-35%) and 38% (25-54%), respectively. B-lymphocytes recovered to normal levels within an average of 48 (21-64) days and 59 (30-66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK-PD model characterized the relationship between venetoclax exposure and reduction in B-lymphocytes and will help design future venetoclax studies in healthy subjects.