TAK-700 (Orteronel)

TAK-700 (Orteronel) is a potent and highly selective human 17,20-lyase inhibitor with IC50 of 38 nM, exhibits >1000-fold selectivity over other CYPs (e.g. 11-hydroxylase and CYP3A4). Phase 3.

Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.[Pubmed:26418412]

Drug Res (Stuttg). 2016 Apr;66(4):217-22.

Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.

Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK-700) in Healthy Male Subjects: A Phase 1, Open-Label, Single-Dose Study.[Pubmed:27163496]

Clin Pharmacol Drug Dev. 2016 May;5(3):180-7.

This study evaluated the absorption, distribution, and excretion of orteronel, an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. Six healthy male subjects received a single 400-mg dose of radiolabeled [(14) C]-orteronel (18.5 kBq). The pharmacokinetics of [(14) C]-radioactivity, orteronel, and the primary metabolite M-I were characterized by ultra-performance liquid chromatography-tandem mass spectrometry, and mass balance recovery of [(14) C]-radioactivity was determined by liquid scintillation counting and accelerator mass spectrometry. Median time to maximum observed concentration of [(14) C]-radioactivity was 2.5 hours (plasma/whole blood) and of orteronel was 1 hour (plasma). Mean terminal half-life for [(14) C]-radioactivity in plasma and whole blood was 9.46 and 7.39 hours, respectively. For [(14) C]-radioactivity, the geometric mean whole blood-to-plasma ratios for maximum observed plasma/whole-blood concentration, area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-last ), and AUC0-inf (AUC from time 0 to infinity) were 1.04, 0.92, and 0.93, respectively. Dose recovery accounted for 95.9% of the administered orteronel dose; the majority of excretion occurred by 96 hours postdose. The principal excretion route was via urine (mean, 77.5%; including 49.7% unchanged drug and 16.3% M-I) compared with 18.4% via feces. Three mild adverse events were reported; none were considered serious or related to orteronel.

A Phase 1, Randomized, Single-Dose Crossover Pharmacokinetic Study to Investigate the Effect of Food Intake on Absorption of Orteronel (TAK-700) in Healthy Male Subjects.[Pubmed:27163497]

Clin Pharmacol Drug Dev. 2016 May;5(3):188-95.

This study aimed to determine the impact of food on the pharmacokinetics of orteronel, an investigational nonsteroidal, reversible selective inhibitor of 17,20-lyase. In this open-label, randomized crossover study, healthy subjects received single doses of orteronel 400 mg with a low-fat meal, a high-fat meal, and under fasting conditions in a randomized sequence. Plasma concentrations of orteronel and its primary M-I metabolite were determined by ultra-performance liquid chromatography, and pharmacokinetic parameters were evaluated using mixed-effects analysis of variance model. Compared with fasting conditions, the oral bioavailability of orteronel was increased under fed conditions. The least-squares mean ratio for area under the plasma concentration-time curve after a low-fat breakfast was 135% (90% confidence interval [CI], 126%-145%) compared with fasting conditions. Similarly, after a high-fat breakfast, the corresponding value was 142% (90%CI, 132%-152%). No unexpected safety concerns were raised with orteronel 400 mg administered in the fasted state or after either a high-fat or a low-fat meal; mild adverse events were experienced by 36% of the healthy male subjects.

TAK-700 (Orteronel) is a potent and highly selective human 17,20-lyase inhibitor with IC50 of 38 nM, exhibits >1000-fold selectivity over other CYPs (e.g. 11-hydroxylase and CYP3A4). Phase 3.

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