Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK‐700) in Healthy Male Subjects: A Phase 1, Open‐Label, Single‐Dose Study

Abstract

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.

Mass Balance of the Indoleamine 2,3‐Dioxygenase Inhibitor Navoximod (GDC-0919) in Rats and Dogs: Unexpected Cyanide Release from Imidazo[5,1-a]isoindole and Species Differences in Glucuronidation

“…Orteronel, which contains a fused dihydro-pyrroloimidazole ring, can potentially undergo a similar cyanide release metabolism like navoximod. However, a thiocyanate metabolite can be easily missed without the radiolabel on the C2-imidazole position (Suri et al, 2016).…”

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

“…Until assay, plasma fractions were extracted from the samples and frozen at −20°C within an hour of collection. As previously described, samples were assayed for orteronel and M‐I via a validated ultra‐performance liquid chromatography (UPLC) with tandem mass spectrometry (MS/MS) assay using positive ion electrospray at PPD, Inc. (mass spectrometer Sciex API 4000, Triple quadrupole LC‐MS/MS; nitrogen gas, 600°C, and ion spray voltage, 2000 V with an acquisition time of 2 minutes; Richmond, Virginia). The multiple‐reaction monitoring ion pair was used to monitor orteronel and its d4 analogue as internal standard as well as M‐I and its d4 analogue as internal standard.…”

“…The investigational agent orteronel (TAK‐700) is a nonsteroidal selective inhibitor of 17,20‐lyase, a key enzyme in the production of steroidal hormones . This agent is predominantly metabolized via the liver and primarily excreted as unchanged drug along with its major metabolite M‐I via feces in rats and urine in monkeys . In a phase 1/2 study and 2 phase 3 trials, orteronel was administered without regard to food in the treatment of metastatic castration‐resistant prostate cancer (mCRPC) …”

Radiolabeled APIs for the Conduct of Human ADME Studies of Oncology Compounds

“…It is completed by using a radioactive tracer (C-14 or H-3) blended with the therapeutic dose of non-radioactive test drug. Its objectives are to determine the route of excretion of compound related material, identify metabolites of a test compound, and describe the exposure of test compound metabolites [1][2][3][4][5][6][7][8][9].…”