Preclinical Assessment of Orteronel®, a CYP17A1 Enzyme Inhibitor in Rats

Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t (A1/2)) of Orteronel with intravenous (i.v.) route was found to be 1.65 +/- A 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 +/- A 3.09 mL/min/kg and 3.94 +/- A 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 +/- A 76.4, 1,764 +/- A 166, 4,652 +/- A 300 and 17,518 +/- A 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t (A1/2) by oral route was found to be similar to 3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.