Expanding the Repertoire for “Large Small Molecules”: Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers

Abstract

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-tert-butyl Chloromethyl Phosphate

“…In order to improve the bioavailability of ABT-199 ( 1 ), a program was initiated to develop methylphosphate prodrug 2 . In the initial stages of the project, several routes were considered and evaluated, but no route gave any distinct advantages over the direct alkylation/deprotection route using di- tert -butyl chloromethyl phosphate ( 3 ) shown in Figure .…”

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

“…The tablet utilizes an amorphous solid dispersion formulation that improves the bioavailability of venetoclax but yields a relatively large tablet (physical size of the 100 mg tablet > 1 g) due to low tablet drug loading. Low drug loading by weight is essential to ensure robust stability and clinical performance of the venetoclax tablets [ 27 ]. This may present a challenge related to swallowability in some populations such as elderly or pediatric patients.…”

“…This may present a challenge related to swallowability in some populations such as elderly or pediatric patients. As part of the continuous efforts to improve the patient experience [ 27 ], additional dosing regimens in the three bioavailability studies presented within were evaluated. This included options to interchange two 50 mg or ten 10 mg tablets for one 100 mg tablet as well as new oral powder formulations that can be administered in liquid or soft food vehicles such as water, apple juice, apple sauce, or yogurt.…”

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination

“…After infectious or other clinically suspected etiologies are excluded, supportive care measures such as anti-emetics and/or anti-motility agents are generally effective and facilitate ongoing treatment in the majority of cases [ 27 ]. Alternative drug formulations are being explored that may improve gastrointestinal tolerance [ 40 , 41 ].…”