A 2023 review article discussed the clinical pharmacokinetics and pharmacodynamics of venetoclax, a BCL-2 inhibitor approved for various hematological malignancies. Venetoclax is noted to have challenging physicochemical properties as it has low aqueous solubility. This has posed challenges for drug formulation and administration. The impact of crushing or grinding venetoclax tablets on its bioavailability was evaluated in a three-way, crossover study in healthy adults (see Table 1). Crushed and finely ground venetoclax tablets had similar bioavailability to intact venetoclax tablets, with only a slightly lower peak plasma concentration, which was not considered clinically significant. Therefore, the authors consider crushing or grinding venetoclax tablets to be a viable alternative method of administration for patients who have difficulty swallowing whole tablets. [1]
A 2022 case report describes a 74-year-old man with acute myeloid leukemia (AML) who experienced increased blood levels of venetoclax after ingesting crushed venetoclax tablets. Initially, the patient achieved remission with induction therapy consisting of idarubicin and cytarabine but later received venetoclax plus azacitidine due to intolerance to potent consolidation therapy. During the first cycle of home treatment, the patient reported difficulty swallowing and consequently crushed the venetoclax tablets for ingestion (approximately from days 19 to 32). However, starting with the second cycle, the patient was able to swallow the tablets whole. The median Cmin during the second cycle remained at 1.46 µg/mL (range 1.34 to 2.68), except on day 2 (day 34; 4.30 µg/mL). The patient developed severe, prolonged neutropenia during the second cycle that was persistently below 100/µL. The elevated plasma venetoclax concentration in this case may be attributed to the crushing of the tablets, as the Cmin of the uncrushed tablet was approximately twice that of the crushed tablet. Since venetoclax is a film-coated tablet and film-coated tablets typically have minimal pharmacokinetic effects when crushed, pharmaceutical companies do not currently have pharmacokinetic data for crushed tablets. Overall, the authors discourage the practice of crushing venetoclax tablets. [2]
Although a retrospective study from 2023 did not address the stability of crushed venetoclax tablets, it did indicate that the crushed form was used in pediatric patients. Venetoclax was administered orally as a tablet once daily with food if tolerated. However, for younger patients who could not swallow pills, the tablets were compounded in an oral hazardous compounding hood by crushing and dissolving them in sterile water to a final concentration of 5 mg/mL. Safety or stability concerns related to the administration of crushed tablets were not discussed. While this study did not assess the stability of Venetoclax being crushed, it highlights the approach taken to accommodate patient needs. [3]
Cincinnati Children’s is currently conducting a pharmacokinetic study of crushed venetoclax tablets dissolved in liquid solution in children and young adults with hematologic malignancies. Patients under 39 years old with any hematologic malignancy, weighing at least 5.5 kg, and having a central line for PK blood draws are eligible for the study. They must be receiving venetoclax, either alone or with other chemotherapeutic agents, as a solution made from crushed tablets administered orally or via NG/G-tube. The study is estimated to be completed in 2026 with 30 enrolled patients. [4], [5]