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.

Fig. 1

Venetoclax mean (± SD) plasma concentration–time profiles for a venetoclax tablet strength bioavailability assessments in Study 1; b venetoclax 7.2% oral powder formulation bioavailability assessments in Study 2; and c vehicle bioavailability assessments of venetoclax 7.2% oral powder formulation in Study 3. All groups in all three studies were administered a dose of 100 mg of venetoclax. N number of participants in each group, SD standard deviation

Fig. 2

Exposure–response quartile plots of venetoclax C_max,ss vs. efficacy endpoints in CLL or AML patients receiving a venetoclax with rituximab (Studies NCT01682616 and NCT02005471); b venetoclax with obinutuzumab (Study NCT02242942); c venetoclax with hypomethylating agent (Studies NCT02203773 and NCT02993523); and d venetoclax with low-dose cytarabine (Studies NCT02287233 and NCT03069352). Note: Mean venetoclax C_max,ss and 28% lower C_max,ss for patients receiving 400 mg of venetoclax with RTX were 1.85 and 1.33 μg/mL, respectively. Mean venetoclax C_max,ss and 28% lower C_max,ss for patients receiving 400 mg of venetoclax with OBZ were 1.58 and 1.14 μg/mL, respectively. Mean venetoclax C_max,ss and 28% lower C_max,ss for patients receiving 400 mg of venetoclax in combination with HMA were 2.83 and 2.04 μg/mL, respectively. Mean venetoclax C_max,ss and 28% lower C_max,ss for patients receiving 600 mg of venetoclax in combination with LDAC were 3.42 and 2.46 μg/mL, respectively. AML acute myeloid leukemia, BEND bendamustine, CHLOR chlorambucil, CLL chronic lymphocytic leukemia, C_max,ss steady-state maximum plasma concentration, CR complete response, CRi complete response with incomplete marrow recovery, HMA hypomethylating agent, LDAC low-dose cytarabine, OBZ obinutuzumab, ORR overall response rate, RTX rituximab, VEN venetoclax