A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels

• Published in: Clinical pharmacology in drug development Vol. 8; no. 4; pp. 529 - 540
• Main Authors: Treijtel, Nicoline, Collins, Christiane, Bruijnsvoort, Michel, Fuhr, Rainard, Ernault, Etienne, Gangaram‐Panday, Shanti, Passier, Paul
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2019; John Wiley and Sons Inc
• Subjects: ASP8477; cytochrome P450; Drug dosages; drug‐drug interaction; Enzymes; inhibition; nonlinear pharmacokinetics; Original Manuscript; Pharmacology; inhibition; ASP8477; cytochrome P450; nonlinear pharmacokinetics; drug-drug interaction
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.660

ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Because ASP8477 shows nonlinear pharmacokinetics, 3 doses (20, 60, and 100 mg) were evaluated. This study revealed changes in exposure (area under the concentration‐time curve) of the probe substrates after treatment with 20, 60, and 100 mg ASP8477, respectively, compared with substrates alone with geometric mean ratios of: midazolam, 119%, 151%, and 158%; losartan, 107%, 144%, and 190%; omeprazole, 213%, 456%, and 610%; and dextromethorphan, 138%, 340%, and 555% (with increasing doses, respectively). Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug‐drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions.