Eluxadoline

Eluxadoline, sold under the brand names Viberzi and Truberzi,^[3] is a medication taken by mouth for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).^[4] It was approved for use in the United States in 2015.^[5] The drug originated from Janssen Pharmaceutica and was developed by Actavis.

Eluxadoline

Clinical data
Pronunciation	Viberzi (/vaɪˈbɜːrzi/ vy-BUR-zee
Trade names	Viberzi, Truberzi
Other names	JNJ-27018966
Routes of administration	By mouth
ATC code	A07DA06 (WHO)
Legal status
Legal status	CA: ℞-only[1] US: Schedule IV[2]
Pharmacokinetic data
Protein binding	81%
Elimination half-life	3.7–6 hours
Excretion	82.2% (feces), <1% (urine)[2]
Identifiers
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
CAS Number	864821-90-9
PubChem CID	11250029
IUPHAR/BPS	7691
DrugBank	DB09272
ChemSpider	9425062
UNII	45TPJ4MBQ1
KEGG	D10403
CompTox Dashboard (EPA)	DTXSID70235589
Chemical and physical data
Formula	C32H35N5O5
Molar mass	569.662 g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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

Contraindications

This drug is contraindicated in case of having:

• Blockage of the gallbladder or a sphincter of Oddi problem
• Problems with excessive alcohol use
• Pancreatitis
• Liver problems
• Chronic or severe constipation^[6]

Adverse effects

Common adverse effects are 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 effects include pancreatitis with a general incidence of 0.3%: higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%).^[7] The risk is even greater in those who do not have a gallbladder and the medication is not recommended in this group.^[8]

In March 2017, the U.S. Food and Drug Administration issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder.^[9] An FDA review found that in such patients, spasm of the sphincter of Oddi may lead to severe pancreatitis.^[10] The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg).^[10] Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder.^[9]

Interactions

Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein OATP1B1, such as ciclosporin, gemfibrozil, certain antiretrovirals, rifampicin, and eltrombopag.^{[medical citation needed]}

Concurrent use of other drugs that cause constipation, such as opioids, alosetron, anticholinergics, and bismuth subsalicylate, is not preferred.^[11]

Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates.^{[medical citation needed]} Co-administration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis.^[2]

Pharmacology

Mechanism of action

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist^[12] that acts locally in the enteric nervous system, possibly decreasing adverse effects on the central nervous system.^[13][14]

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 C_max 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. 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.^[15]

Following a 100 mg dose of eluxadoline, the C_max was about 2 to 4 ng/ml and AUC was 12 to 22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the C_max by 50% and AUC by 60%.^[2]

Chemistry

Synthesis

The synthesis of eluxadoline was published in 2006.^[16]