Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet

Abstract

Background and Objective Venetoclax is an approved BCL-2 inhibitor, currently under evaluation in different hematological malignancies in adult and pediatric populations. Venetoclax is available as 10, 50, and 100 mg tablets. To provide an alternative to patients who find taking the commonly prescribed 100 mg tablet a challenge, the interchangeability of lower-strength tablets with the 100 mg tablet was investigated. Additionally, newly developed oral suspension powder formulations to facilitate dosing in pediatrics were evaluated. Methods Pharmacokinetic data from 80 healthy female participants from three phase I studies were utilized to evaluate the bioavailability of (1) 10 and 50 mg tablets relative to a 100 mg tablet; (2) 0.72 and 7.2% (drug to total weight) oral powder formulations relative to the 100 mg tablet; and (3) oral powder formulations administered using different vehicles (apple juice, apple sauce, and yogurt) relative to water under fed conditions. Results Bioavailability assessments at a 100 mg dose of venetoclax demonstrated bioequivalence across the 10, 50, and 100 mg tablet strengths. Oral powder formulations met the bioequivalence criteria (0.80–1.25) with respect to area under the concentration–time curve to time of the last measurable concentration (AUC t ) and to infinite time (AUC ∞ ) but exhibited a slightly lower maximum plasma concentration ( C max ). Exposure–response analyses were utilized to demonstrate that the lower C max observed with the powder formulations is not clinically meaningful. The delivery vehicles tested did not affect the bioavailability of venetoclax oral powder formulations. Conclusions The smaller-sized tablets (10 and 50 mg) and the newly developed oral powder formulations of venetoclax can be used interchangeably with the 100 mg tablets to improve the patients’ experience, while maintaining adequate exposure. Clinical Trials Identifiers NCT01682616, 11 September 2012; NCT02005471, 9 December 2013; NCT02242942, 17 September 2014; NCT02203773, 30 July 2014; NCT02287233, 10 November 2014; NCT02993523, 15 December 2016; NCT03069352, 3 March 2017. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-022-01172-4.

Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials

“…The 2‐compartment PK model with first‐order elimination was extended to include 3 transit compartments for an accurate description of the absorption phase. The current model captures venetoclax maximum concentration better than the legacy model (Figure S1) based on just 505 subjects, 8 and this absorption model is consistent with the venetoclax formulation concept and its biopharmaceutics 21 . Estimated effects of moderate and strong CYP3A inhibitors on CL/F, food effect, and dose nonlinearity were similar to the previous venetoclax population PK model 8 …”

“…The current model captures venetoclax maximum concentration better than the legacy model (Figure S1) based on just 505 subjects, 8 and this absorption model is consistent with the venetoclax formulation concept and its biopharmaceutics. 21 Estimated effects of moderate and strong CYP3A inhibitors on CL/F, food effect, and dose nonlinearity were similar to the previous venetoclax population PK model. 8 With extensive data across multiple indications and populations, our analyses provide an improved understanding of factors affecting venetoclax PK.…”

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B‐cell lymphoma‐2 inhibitor

“…The three strengths were evaluated in a phase I bioavailability study and were bioequivalent at the 100 mg dose. 14 The impact of crushing or grinding venetoclax tablets on its bioavailability was recently evaluated in a three-way, crossover study in 15 healthy adult females. 58 Crushed and finely ground venetoclax tablets had similar bioavailability to the intact venetoclax tablets as the venetoclax AUC for both regimens met the bioequivalence criteria.…”

“…The 10 and 50 mg are predominantly used during ramp‐up. The three strengths were evaluated in a phase I bioavailability study and were bioequivalent at the 100 mg dose 14 …”

“…The lower C max is not expected to affect venetoclax efficacy and exposure–response analyses demonstrated the lack of significant relationships between venetoclax C max and clinical efficacy in AML and CLL. Clinical responses to venetoclax have been shown to correlate with AUC ss or C avg , for which the oral powder formulation meets the bioequivalence criteria 14 . The effect of different dosing vehicles (water, apple juice, apple sauce, and yogurt) on the bioavailability of the oral powder formulations at a dosage of 100 mg once daily was also evaluated in a phase I bioavailability study.…”