Orteronel

IC50: Orteronel inhibited monkey 17,20-lyase and 17-hydroxylase activities with IC50 values of 27 and 38 nmol/L, respectively [1].

Orteronel is an androgen biosynthesis inhibitor. It selectively inhibits the enzyme CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity (http://en.wikipedia.org/wiki/Orteronel).

In vitro: Orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC50 value of orteronel for cortisol was about 3-fold higher than that for DHEA. Moreover, in human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys [1].

In vivo: After Orteronel single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC [1].

Clinical trial: Takeda Pharmaceutical Company Limited announced that it has voluntarily decided to end the development program for orteronel (TAK-700) for prostate cancer. The decision follows the results of two Phase 3 clinical trials in metastatic, castration resistant prostate cancer (mCRPC). The studies found while orteronel plus prednisone could extend the time patients lived before their cancer progressed, it did not extend overall survival in these patients. After careful consideration of the data from these trials, the company has determined that the drug has not demonstrated a clinical profile sufficient to move forward in mCRPC, given the availability of other therapies.

Reference:
[1] Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S, Miki H, Tasaka A, Kusaka M. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012;129(3-5):115-28.


Orteronel Switch Maintenance Therapy in Metastatic Castration Resistant Prostate Cancer After First-Line Docetaxel: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (SAKK 08/11).[Pubmed:27457964]

Prostate. 2016 Dec;76(16):1519-1527.

BACKGROUND: We tested whether a switch maintenance treatment with Orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration-resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel. METHODS: Men with mCRPC and non-progressive disease after a cumulative dose of >/=300 mg/m(2) docetaxel for first line treatment were randomized 1:1 to receive Orteronel 300 mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on Orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%). RESULTS: Forty-seven patients (23 Orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of Orteronel. Median EFS was 8.5 months with Orteronel and 2.9 months with placebo (P = 0.001; HR 0.32; 95%CI 0.15-0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P = 0.02; HR 0.42; 95%CI 0.20-0.91) in the Orteronel and placebo arm, respectively. PSA decline >/=50% was seen in 57% on Orteronel and 4% on placebo. Toxicity was mainly mild, one patient on Orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis. CONCLUSIONS: Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research. Prostate 76:1519-1527, 2016. (c) 2016 Wiley Periodicals, Inc.

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.

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer.[Pubmed:27826831]

Invest New Drugs. 2017 Feb;35(1):87-94.

Introduction Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by Orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of Orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of Orteronel in women; escalation was via standard 3 + 3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47-73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to Orteronel included grade 1-2 nausea (n = 4) and bone pain (n = 3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n = 2). The only grade 3 AE was hypertension (n = 2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of Orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer.

Orteronel is a highly selective inhibitor of human 17,20-lyase with IC50 of 38 nM, and exhibits >1000-fold selectivity over other CYPs such as 11-hydroxylase and CYP3A4.

Orteronel,566939-85-3,Natural Products,17,20-lyase, buy Orteronel , Orteronel supplier , purchase Orteronel , Orteronel cost , Orteronel manufacturer , order Orteronel , high purity Orteronel