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.

Semimechanistic Modeling to Guide Venetoclax Coadministration with Ritonavir and Digoxin

“…[25][26][27][28][29] To avoid the risk of lymphopenia, an on-target effect of venetoclax, a single subtherapeutic dose (100 mg) of venetoclax was studied in female healthy volunteers in the digoxin drug-interaction study. 30 In that study, digoxin C max and AUC were increased by 35% and 9%, respectively, with no changes in half-life or renal clearance. 20 These clinical results form the basis for our assumption that the increases in digoxin exposures were due to venetoclax inhibition of…”

How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS‐CoV‐2 Pandemic

“…B-lymphocytes recover to normal levels within an average of 60 days from venetoclax discontinuation. 83 , 91 The disadvantage of venetoclax treatment is the need for frequent access to the hospital during the ramp-up phase to prevent tumor lysis syndrome (TLS). 58 In addition, venetoclax treatment has a relatively high risk of neutropenia during the first 3 months, though it does not translate into a high rate of infections and can be easily prevented through the use of G-CSF.…”

A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold‐labeled venetoclax, from chemistry to the clinic

“… 5 Venetoclax pharmacokinetics and pharmacodynamics have been well‐characterized in healthy volunteers as well as in patients with chronic lymphocytic leukemia, acute myelogenous leukemia, multiple myeloma, or non‐Hodgkin lymphoma. 6 , 7 , 8 , 9 , 10 , 11 , 12 Venetoclax reaches C max 6–8 h after dosing, and has a terminal half‐life of 16 h. 13 , 14 Venetoclax is predominantly metabolized by the CYP3A4 enzyme. 15 , 16 The relationship between venetoclax exposure and clinical responses has been previously described.…”

“…compound (i.e., low solubility and low permeability) with high nonspecific binding and is available as an oral tablet 5 . Venetoclax pharmacokinetics and pharmacodynamics have been well‐characterized in healthy volunteers as well as in patients with chronic lymphocytic leukemia, acute myelogenous leukemia, multiple myeloma, or non‐Hodgkin lymphoma 6–12 . Venetoclax reaches C max 6–8 h after dosing, and has a terminal half‐life of 16 h 13,14 .…”