Eluxadoline

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Eluxadoline
Eluxadoline.svg
Eluxadoline ball-and-stick model.png
Systematic (IUPAC) name
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
Clinical data
Trade names Viberzi
Legal status
Routes of
administration		 Oral
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
Molecular mass 569.6508 g/mol
  • CC1=CC(=CC(=C1CC(C(=O)N(CC2=CC(=C(C=C2)OC)C(=O)O)C(C)C3=NC=C(N3)C4=CC=CC=C4)N)C)C(=O)N
  • InChI=1S/C32H35N5O5/c1-18-12-23(29(34)38)13-19(2)24(18)15-26(33)31(39)37(17-21-10-11-28(42-4)25(14-21)32(40)41)20(3)30-35-16-27(36-30)22-8-6-5-7-9-22/h5-14,16,20,26H,15,17,33H2,1-4H3,(H2,34,38)(H,35,36)(H,40,41)/t20-,26-/m0/s1
  • Key:QFNHIDANIVGXPE-FNZWTVRRSA-N


Eluxadoline (INN, USAN) (brand name Viberzi vye-BER-zee; former developmental code name JNJ-27018966) is a novel, 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.

Mechanism of action

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

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

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

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

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:

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

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

This drug should not be taken in case of having:

See also

References

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  5. ↑ [1], Process of the Preparation of Opioid modulators.
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  8. ↑ Limbo AJ, et al. Eluxadoline in Irritable Bowel Syndrome with Diarrhea. NEJM 2016;374:242-53
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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