Eluxadoline
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| Systematic (IUPAC) name | |
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5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid
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| Clinical data | |
| Trade names | Viberzi |
| Routes of administration |
Oral |
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| Pharmacokinetic data | |
| Protein binding | 81% |
| Biological half-life | 3.7–6 hours |
| Excretion | 82.2% (feces), <1% (urine)[1] |
| Identifiers | |
| CAS Number | 864821-90-9 |
| PubChem | CID 11250029 |
| IUPHAR/BPS | 7691 |
| ChemSpider | 9425062 |
| Chemical data | |
| Formula | C32H35N5O5 |
| Molar mass | 569.6508 g/mol |
| 3D model (Jmol) | Interactive image |
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Eluxadoline (INN, USAN) (brand name Viberzi vye-BER-zee; former developmental code name JNJ-27018966) is an orally-active drug approved for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D). It was approved for use by the United States Food and Drug Administration on May 27, 2015.[2] The drug originated from Janssen Pharmaceutica and was developed by Actavis.
Contents
Mechanism of action[edit]
Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system, possibly decreasing adverse effects on the central nervous system.[3][4]
Synthesis[edit]
The synthesis of eluxadoline was extensively discussed in the patent No. WO2006099060 A2, with the title : "Process for the preparation of opioid modulators" which was published in Sept. 2006[5]
Pharmacokinetics[edit]
In the in vitro studies, eluxadoline was found to be transported by OAT3 (SLC22A8), OATP1B1 (SLCO1B1) and BSEP (ABCB11) at the highest concentrations tested (400 ng/ml which is 162-fold larger than the observed Cmax of the highest therapeutic dose of 100 mg). However, it was not to be transported by OCT1 POU2F1, OAT1 Organic anion transporter 1, OCT2, OATP1B3 (SLCO1B3), P-gp (P-glycoprotein), or BCRP (ABCG2).
Multidrug resistance-associated protein 2 (MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. Also in the in vitro studies, it was observed that eluxadoline is an in vivo substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of cytochrome P450 enzymes was observed.[6]
Following a 100 mg dose of eluxadoline, the Cmax was about 2 to 4 ng/ml and AUC was 12-22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the Cmax by 50% and AUC by 60%.[1]
Dosing and administration[edit]
Eluxadoline is available as 75 and 100 mg in the form of tablets.
Its use may lead to constipation. Discontinue eluxadoline if the constipation lasts for more than 4 days.[1]
Drug interactions[edit]
Elevated concentrations of eluxadoline were observed with coadministraion of OATP1B1 inhibitors such as:
Also, concurrent use of other drugs that cause constipation is not preferred, such as:
- Opioids
- Alosetron
- Anticholinergics
- Bismuth subsalicylate, potentially dangerous synergism.[7]
Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Also, coadministration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis.[1]
Adverse effects[edit]
Common adverse effects in the two phase III clinical trials were constipation and nausea but rates of discontinuation due to constipation were low for both eluxadoline and placebo. Rare adverse effects: fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effect in a clinical trial was pancreatitis with a general incidence of 0.3% - higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%).[8]
Contraindications[edit]
This drug should not be taken in case of having:
- Blockage of the gallbladder or a sphincter of Oddi problem
- Problems with alcohol abuse
- Pancreatitis
- Liver problems
- Chronic or severe constipation[9]
See also[edit]
References[edit]
- ^ a b c d "Viberzi (eluxadoline) Tablets, for Oral Use, CIV. Full Prescribing Information". Actavis Pharma, Inc. Parsippany, NJ 07054 USA. Retrieved 26 December 2015.
- ^ "FDA approves two therapies to treat IBS-D". www.fda.gov. Retrieved 2015-06-01.
- ^ "Actavis Announces FDA Acceptance for Filing of NDA for Eluxadoline". www.drugs.com. Retrieved 2015-06-01.
- ^ "FDA Approves Viberzi (eluxadoline) for Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults". www.drugs.com. Retrieved 2015-06-01.
- ^ [1], Process of the Preparation of Opioid modulators.
- ^ Davenport, J. Michael; Covington, Paul; Bonifacio, Laura; McIntyre, Gail; Venitz, Jürgen (2015). "Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline". The Journal of Clinical Pharmacology. 55 (5): 534–542. doi:10.1002/jcph.442. ISSN 0091-2700.
- ^ "bismuth subsalicylate". reference.medscape.com. Retrieved 2016-05-10.
- ^ Limbo AJ, et al. Eluxadoline in Irritable Bowel Syndrome with Diarrhea. NEJM 2016;374:242-53
- ^ "Viberzi Information from Drugs.com". www.drugs.com. Retrieved 2015-06-01.
