Evaluation of the Pharmacokinetics of Felcisetrag (TAK-954), a 5-HT
5-HT4
cytochrome P450 3A4
drug-drug interaction
felcisetrag
pharmacokinetics
safety
Journal
Clinical pharmacology in drug development
ISSN: 2160-7648
Titre abrégé: Clin Pharmacol Drug Dev
Pays: United States
ID NLM: 101572899
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
25
07
2019
accepted:
10
10
2021
pubmed:
7
1
2022
medline:
5
4
2022
entrez:
6
1
2022
Statut:
ppublish
Résumé
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.
Substances chimiques
Cytochrome P-450 CYP3A Inhibitors
0
Itraconazole
304NUG5GF4
Serotonin
333DO1RDJY
Cytochrome P-450 CYP3A
EC 1.14.14.1
CYP3A4 protein, human
EC 1.14.14.55
Banques de données
ClinicalTrials.gov
['NCT03173170']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
142-149Informations de copyright
© 2022, The American College of Clinical Pharmacology.
Références
Azimuddin K, Rosen L, Reed JF 3rd, et al. Readmissions after colorectal surgery cannot be predicted. Dis Colon Rectum. 2001;44(7):942-946.
Goodney PP, Stukel TA, Lucas FL, Finlayson EV, Birkmeyer JD. Hospital volume, length of stay, and readmission rates in high-risk surgery. Ann Surg. 2003;238(2):161-167.
Gero D, Gié O, Hübner M, Demartines N, Hahnloser D. Postoperative ileus: in search of an international consensus on definition, diagnosis, and treatment. Langenbecks Arch Surg. 2017;402(1):149-158.
Hedrick TL, McEvoy MD, Mythen MMG, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on postoperative gastrointestinal dysfunction within an enhanced recovery pathway for elective colorectal surgery. Anesth Analg. 2018;126(6):1896-1907.
Kraft M, Maclaren R, Du W, Owens G. Alvimopan (Entereg) for the management of postoperative ileus in patients undergoing bowel resection. P T. 2010;35 (1):44-49.
Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e6329.
Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev. 2017;8(8):CD012763.
Johnson MD, Walsh RM. Current therapies to shorten postoperative ileus. Cleve Clin J Med. 2009;76(11):641-648.
Nguyen NQ, Chapman MJ, Fraser RJ, Bryant LK, Holloway RH. Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness. Crit Care Med. 2007;35(2):483-489.
Hancox JC, Hasnain M, Vieweg WV, et al. Erythromycin, QTc interval prolongation, and torsade de pointes: case reports, major risk factors and illness severity. Ther Adv Infect Dis. 2014;2(2):47-59.
Beattie DT, Armstrong SR, Vickery RG, 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.
Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012;35(7):745-767.
Melnyk M, Casey RG, Black P, Koupparis AJ. Enhanced recovery after surgery (ERAS) protocols: time to change practice? Can Urol Assoc J. 2011;5(5):342-348.
Venara A, Neunlist M, Slim K, et al. Postoperative ileus: pathophysiology, incidence, and prevention. J Visc Surg. 2016;153(6):439-446.
Keller DS, Bankwitz B, Woconish D, et al. Predicting who will fail early discharge after laparoscopic colorectal surgery with an established enhanced recovery pathway. Surg Endosc. 2014;28(1):74-79.
Grass F, Slieker J, Jurt J, et al. Postoperative ileus in an enhanced recovery pathway-a retrospective cohort study. Int J Colorectal Dis. 2017;32(5):675-681.
Chapman MJ, Jones KL, Almansa C, et al. Blinded, double-dummy, parallel-group, phase 2a randomized clinical trial to evaluate the efficacy and safety of a highly selective 5-hydroxytryptamine type 4 receptor agonist in critically Ill patients with enteral feeding intolerance. JPEN J Parenter Enteral Nutr. 2021;45(1):115-124.
Camilleri M, Atieh J. New developments in prokinetic therapy for gastric motility disorders. Front Pharmacol. 2021:12:711500.
Chedid V, Brandler J, Arndt K, et al. Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis. Aliment Pharmacol Ther. 2021;53(9):1010-1020.
Camilleri M. New drugs on the horizon for functional and motility gastrointestinal disorders. Gastroenterology. 2021.161:761-764.
Kennedy JM, van Rij AM, Spears GF, Pettigrew RA, Tucker IG. Polypharmacy in a general surgical unit and consequences of drug withdrawal. Br J Clin Pharmacol. 2000;49(4):353-362.
Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother. 2002;46(1):160-165.
Greenblatt DJ, Harmatz JS. Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. Br J Clin Pharmacol. 2015;80(3):342-350.