Expanding the Repertoire for “Large Small Molecules”: Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers
Year: 2021
Type: article
Study design: Clinical Trial
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.
Source: Molecular Cancer Therapeutics
Authors: Ahmed Hamed Salem, Zhi-Fu Tao, Orlando F. Bueno, Jie Chen, Shuang Chen, Rohinton Edalji, Steven W. Elmore, Keith M. Fournier, Kaid C. Harper, Richard Hong, Gary J. Jenkins, Jianguo Ji, Russell A. Judge, John C. Kalvass, Russell C. Klix, Yi-Yin Ku, Joel D. Leverson, Richard A. Marks, Kennan C. Marsh, Rajeev M. Menon, Chang H. Park, Darren C. Phillips, Yu-Ming Pu, Saul H. Rosenberg, Yeshwant D. Sanzgiri, Ahmad Y. Sheikh, Yi Shi, Deanne Stolarik, Ahmed A. Suleiman, Xilu Wang, Geoff G.Z. Zhang, Nathaniel D. Catron, Andrew J. Souers
Institutions: Ain Shams University, AbbVie (United States)
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: AbbVie
OpenAlex ID: W3140100778