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Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats
Mohd Zainuddin1, A B Vinod1, Sandip Dhondiram Gurav1
1Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore, 560 022, India.
Abstract:
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 ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 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 ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.
Insights
Orteronel, a CYP17A1 inhibitor for prostate cancer, shows good metabolic stability and high oral bioavailability in rats. Its primary elimination route is via urine, indicating favorable pharmacokinetic properties.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Orteronel (TAK-700) is a novel, selective CYP17A1 inhibitor.
- CYP17A1 is implicated in prostate tumor growth.
- Orteronel is in Phase-III trials for metastatic castration-resistant prostate cancer.
Purpose of the Study:
- Assess Orteronel's permeability and metabolic stability.
- Identify major cytochrome P450 enzymes (CYPs) involved in its metabolism.
- Evaluate Orteronel's pharmacokinetics and excretion in rats.
Main Methods:
- In vitro studies using liver microsomes (preclinical and human).
- Pharmacokinetic analysis in Sprague-Dawley rats following intravenous and oral administration.
- Excretion studies in rats.
Main Results:
- Orteronel demonstrated stability across tested liver microsomes.
- Intravenous administration showed a half-life of 1.65 ± 0.22 h, clearance of 27.5 ± 3.09 mL/min/kg, and volume of distribution of 3.94 ± 0.85 L/kg.
- Oral administration exhibited rapid absorption, dose-proportional pharmacokinetics, a mean half-life of ~3.5 h, and bioavailability ranging from 69-89%.
Conclusions:
- Orteronel possesses favorable metabolic stability and pharmacokinetic properties.
- The drug is primarily eliminated via urine.
- These findings support its continued clinical development for prostate cancer.
