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Felcisetrag Sale

(Synonyms: TD-8954) 目录号 : GC63682

Felcisetrag (TD-8954) 是一种具有口服活性,有效和选择性 5-HT4 受体激动剂,具有胃肠道促动力特性。Felcisetrag 对人类重组 5-HT4(c) (h5-HT4(c)) 受体具有高亲和力 (pKi =9.4)。

Felcisetrag Chemical Structure

Cas No.:916075-84-8

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5 mg
¥4,320.00
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10 mg
¥7,200.00
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产品描述

Felcisetrag (TD-8954) is an orally active, potent and selective 5-HT4 receptor agonist with gastrointestinal prokinetic properties. Felcisetrag has high affinity (pKi =9.4) for human 5-HT4(c) receptors.

Felcisetrag produces an elevation of cAMP in HEK-293 cells expressing the h5-HT4(c) receptor (pEC50 = 9.3), and contracts the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC50 = 8.6). Felcisetrag has moderate intrinsic activity in the vitro assays[1].

Felcisetrag (0.03~3 mg/kg; s.c.) increases the colonic transit of carmine red dye, reducing the time taken for its excretion[1].Felcisetrag (0.03~10 mg/kg; intraduodenal administration) evokes a dose-dependent relaxation of the esophagus[1].Felcisetrag (10 and 30 μg/kg; p.o) produces an increase in contractility of the antrum, duodenum, and jejunum[1].

[1]. Beattie DT, et al. The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties. Front Pharmacol. 2011;2:25.

Chemical Properties

Cas No. 916075-84-8 SDF
别名 TD-8954
分子式 C25H37N5O3 分子量 455.59
溶解度 DMSO : 50 mg/mL (109.75 mM; ultrasonic and warming and heat to 60°C) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.195 mL 10.9748 mL 21.9496 mL
5 mM 0.439 mL 2.195 mL 4.3899 mL
10 mM 0.2195 mL 1.0975 mL 2.195 mL
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Research Update

Evaluation of the Pharmacokinetics of Felcisetrag (TAK-954), a 5-HT4 Receptor Agonist, in the Presence and Absence of Itraconazole, a Potent CYP3A4 Inhibitor

Clin Pharmacol Drug Dev 2022 Feb;11(2):142-149.PMID:34989180DOI:10.1002/cpdd.1046.

The 5-hydroxytryptamine type-4 receptor agonist Felcisetrag (TAK-954) is being investigated for improving gastrointestinal motility in postoperative gastrointestinal dysfunction. Polypharmacy often occurs in this setting, and as in vitro data indicate, Felcisetrag is primarily metabolized by cytochrome P450 (CYP) 3A4, its CYP3A4-mediated drug-drug interaction potential requires consideration. This phase 1, fixed-sequence, open-label, crossover trial (ClinicalTrials.gov identifier NCT03173170) investigated the effect of itraconazole, a potent CYP3A4 inhibitor, on Felcisetrag pharmacokinetics in healthy adults. Over 2 study periods (period 1, 6 days; period 2, 9 days), participants received a single Felcisetrag 0.2-mg intravenous dose (day 1, period 1; and day 4, period 2), and once-daily oral itraconazole 200-mg doses (days 1-8, period 2). For Felcisetrag alone, Felcisetrag total systemic exposure was lower than with itraconazole coadministration. The geometric mean ratio for area under the plasma concentration-time curve from time 0 to infinity of Felcisetrag plus itraconazole: Felcisetrag alone was 1.49 (90% confidence interval, 1.39-1.60). Peak exposure was similar between regimens (geometric mean ratio, 1.06; 90% confidence interval, 0.96-1.18), and both treatments were well tolerated. These data suggest limited CYP3A4-mediated drug-drug interaction inhibition for Felcisetrag.

The Effect of Hepatic Impairment on the Pharmacokinetics of Intravenously Administered Felcisetrag (TAK-954)

J Clin Pharmacol 2022 Aug;62(8):1006-1017.PMID:35253917DOI:10.1002/jcph.2044.

Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal dysfunction. The safety, tolerability, and pharmacokinetics (PK) of intravenous (i.v.) Felcisetrag have been studied, but little is known about the effect of hepatic impairment on the PK of the drug. This phase 1, non-randomized, open-label study compared the PK of a single 60-minute i.v. infusion of Felcisetrag between healthy individuals (n = 8) and patients with moderate (n = 10) or severe (n = 7) hepatic impairment. The primary study end points were the total and free maximum observed plasma concentration of Felcisetrag at the end of infusion (Cmax ), area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUClast ), and AUC from time 0 to infinity (AUCinf ). Concentration-time profiles of Felcisetrag were similarly shaped between groups but revealed lower concentrations of total plasma Felcisetrag with increasing severity of hepatic impairment, whereas concentrations of free Felcisetrag increased. The ratios of AUClast and AUCinf for patients with severe hepatic impairment were up to 29.3% lower for total Felcisetrag and up to 29.2% higher for free Felcisetrag than found in healthy individuals (P < .05). Infusions were well tolerated with no discontinuations, severe adverse events, or deaths during the study. Overall, the effect of hepatic impairment on exposure to Felcisetrag was minimal, suggesting that dose adjustment may be unnecessary in patients with hepatic impairment.

Randomised study: effects of the 5-HT4 receptor agonist Felcisetrag vs placebo on gut transit in patients with gastroparesis

Aliment Pharmacol Ther 2021 May;53(9):1010-1020.PMID:33711180DOI:10.1111/apt.16304.

Background: Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction. Aim: To evaluate pharmacokinetics and pharmacodynamics of Felcisetrag, a highly selective 5-HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids. Methods: Single-centre, placebo-controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of Felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99m Tc-egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111 In-charcoal delivered in methacrylate-coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2 . Statistical analysis used baseline parameters as covariates (ANCOVA). Results: Patients (22 idiopathic, 14 diabetic gastroparesis) were randomised to Felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, Felcisetrag significantly accelerated gastric emptying T1/2 , colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2 ) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg Felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG. Conclusion: I.V. Felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577.

Clinical and Nonclinical Disposition and In Vitro Drug-Drug Interaction Potential of Felcisetrag, a Highly Selective and Potent 5-HT4 Receptor Agonist

Eur J Drug Metab Pharmacokinet 2022 May;47(3):371-386.PMID:35157234DOI:10.1007/s13318-021-00751-8.

Background and objective: Felcisetrag (previously TAK-954 or TD-8954) is a highly selective and potent 5-HT4 receptor agonist in clinical development for prophylaxis and treatment of postoperative gastrointestinal dysfunction (POGD). The rat, dog, and human absorption, distribution, metabolism, and excretion (ADME) properties of Felcisetrag were investigated. Methods: The metabolism and victim and perpetrator drug interaction potentials towards cytochrome P450s (CYP) and transporters were determined using in vitro models. The excretion, metabolite profile, and pharmacokinetics were determined during unlabeled and radiolabeled ADME studies in rat and dog for comparison with human. Due to a low clinical dose (0.5 mg) and radioactivity (~ 1.5 μCi), a combination of liquid scintillation counting and accelerator mass spectrometry was used for analysis of samples in this study. Results: The ADME properties, including metabolite profile, for Felcisetrag are generally conserved across species. Felcisetrag is primarily cleared through renal excretion (0.443) and metabolism in humans (0.420), with intact parent as the predominant species in circulation. There are multiple metabolites, each representing < 10% of the circulating radioactivity, confirming no metabolites in safety testing (MIST) liabilities. Metabolites were also detected in animals. The potential for major CYP- and transporter-based drug-drug interaction (DDI) of Felcisetrag as a victim or perpetrator is considered to be low. Conclusions: Felcisetrag is primarily cleared in humans through renal excretion. Although the metabolism of Felcisetrag is primarily through CYP3A, the potential for clinically relevant DDI as a victim is significantly reduced as metabolism plays a minor role in the overall clearance.