The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

• Published in: Biopharmaceutics & drug disposition Vol. 39; no. 8; pp. 388 - 393
• Main Authors: Pike, Andy, Flanagan, Neil J., Storer, R. Ian, Swain, Nigel A., Tseng, Elaine
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01.09.2018
• Subjects: Bile; Excretion; Intravenous administration; Molecular weight; OATP; organic anion‐transporting polypeptides; pharmacokinetics; Physicochemical properties; Polypeptides; Residual effects; Sodium channels (voltage-gated); Solutol; Zwitterions
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2156

PF‐06456384 is an extremely potent and selective blocker of the Nav1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Nav1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.