μ-opioid receptor ( Ki = 0.77 nM ); δ-opioid receptor ( Ki = 4.4 nM ); κ-opioid receptor ( Ki = 40 nM )
Alvimopan dihydrate targets the mu‑opioid receptor (μ‑opioid receptor). It has considerably greater binding affinity for mu‑opioid receptors than for delta‑ and kappa‑opioid receptors (specific IC50, Ki, EC50 or DC50 values not provided in this review) [1].

Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Upon testing at various non-opioid receptors, ion channels, and enzymes, alvimopan (1 or 10 μM) does not exhibit any noteworthy affinity[2].

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Alvimopan only counteracts morphine-induced analgesia in animals at relatively high dosages; in order for the drug to cross the blood-brain barrier, very high plasma concentrations are required. Alvimopan is about 200 times more effective at blocking peripheral than central μ-receptors after intravenous injection. Alvimopan is also very active when taken orally. Alvimopan administered intravenously to dogs increased plasma area under the concentration-time curve and peak plasma concentrations in a dose-dependent manner. Oral doses up to 100 mg/kg, however, resulted in low plasma concentrations (mean C_max = 92.9 ng/ml) due to poor systemic absorption, which led to an oral bioavailability of about 0.03%. In dogs and rabbits, the half-life of alvimopan is thought to be roughly 10 minutes following intravenous administration[1].
In five multicenter, randomized, double‑blind, placebo‑controlled trials in patients undergoing partial large‑bowel or small‑bowel resection with primary anastomosis (or total abdominal hysterectomy), Alvimopan dihydrate (12 mg orally preoperatively, then twice daily for up to 7 days or until discharge) significantly accelerated GI recovery compared with placebo: time to recovery of upper and lower GI function (GI‑3 composite endpoint: toleration of solid food plus first flatus or first bowel movement, whichever occurred first) was shortened by 10.7 to 26.1 hours; patients receiving alvimopan were discharged 13 to 21 hours sooner than placebo. Alvimopan did not reverse opioid analgesia [1].
In a 21‑day randomized placebo‑controlled study (n=168) of patients with opioid‑induced bowel dysfunction (OBD) receiving chronic opioids, Alvimopan dihydrate 1 mg once daily resulted in a significantly higher percentage of patients (54%) having at least one bowel movement within 8 hours after each daily dose over 21 days compared with placebo (29%, P<0.001); median time to first bowel movement after the first dose was 3 hours for the 1 mg group vs. 21 hours for placebo (P<0.001) [1].
In a 6‑week dose‑finding study (n=522) in patients with non‑cancer pain and OBD, Alvimopan dihydrate (0.5 mg twice daily, 1 mg once daily, or 1 mg twice daily) produced statistically significant increases in mean weekly spontaneous bowel movements over the first 3 weeks compared with placebo (P<0.001 for all). The 0.5 mg twice‑daily regimen had the best benefit‑to‑risk profile. Alvimopan did not antagonize opioid analgesia [1].

Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Tested at both 1 and 10 μM, alvimopan does not exhibit any noteworthy affinity for a wide variety of non-opioid receptors, ion channels, or enzymes.

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Alvimopan dihydrate is administered orally. Pharmacokinetic parameters in healthy subjects: peak plasma concentration occurs approximately 2 h after ingestion; oral bioavailability is about 6% (range 1‑19%). Due to its moderately large molecular weight (460.6) and low lipophilicity, it does not cross the blood‑brain barrier. The major metabolite is ADL08‑0011, formed via intestinal rather than hepatic metabolism. Terminal half‑life of alvimopan and its metabolite is 10‑18 h. High‑fat meals decrease the extent and rate of absorption (clinical significance unknown). Age and sex do not affect pharmacokinetics; no dosage adjustments are needed. Approximately 2% of the dose is excreted unchanged in urine; renal clearance accounts for ~30% of total plasma clearance. Biliary secretion is the primary elimination pathway; hepatic metabolism plays no significant role. At doses up to 24 mg twice daily for 7 days, alvimopan did not cause clinically significant QTc prolongation (higher doses not studied) [1].

Alvimopan dihydrate is generally well tolerated. Commonly reported adverse events in surgical patients (n=1365) include nausea (9.7% vs. placebo 7.6%), flatulence (8.7% vs. 7.7%), hypokalemia (6.9% vs. 7.5%), dyspepsia (5.9% vs. 4.8%), anemia (5.4% for both), urinary retention (3.5% vs. 2.3%), and back pain (3.4% vs. 2.6%). In chronic OBD studies, adverse effects (abdominal cramping, nausea, vomiting, diarrhea, flatulence) were transient and mild‑to‑moderate, resolving within one week. In patients receiving chronic opioids, alvimopan may precipitate dose‑related, localized gut‑specific withdrawal [1].
Long‑term safety study (12 months, 0.5 mg twice daily) showed a higher incidence of myocardial infarction (2.6% vs. placebo 1.12%), neoplasms (2.8% vs. 0.7%), and fractures compared with placebo; a causal relationship has not been established. In bowel‑resection surgery trials (6 mg twice daily), the most common adverse events were nausea, vomiting, and hypotension; nausea/vomiting occurred more frequently with placebo, and hypotension showed no difference [1].
Contraindications: patients who have been receiving therapeutic doses of opioids for more than 7 consecutive days. Not recommended for severe hepatic impairment, end‑stage renal disease, or surgery to correct complete bowel obstruction. Pregnancy Category B [1].

[1]. P T. 2008 Oct; 33(10): 574, 580-583.

[2]. Therapeutics. 2009, 1: 199-213.

Alvimopan is a synthetic trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine compound with peripherally selective opioid μ-receptor antagonistic activity. Alvimopan is a selective competitive antagonist of μ-opioid receptors in human intestinal myenteric neurons, submucosal neurons, and lamina propria immune cells. After administration, the drug binds to μ-opioid receptors in the intestine, thereby reversing opioid-induced intestinal motility disorders. Alvimopan is approximately 3 to 9 times more potent than naloxone.
See also: Alvimopan (note moved to).

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Alvimopan dihydrate (Entereg) was FDA‑approved in May 2008 for in‑hospital, short‑term use (maximum 15 doses) to accelerate GI recovery after partial large‑ or small‑bowel resection with primary anastomosis. It is available only under a Risk Evaluation and Mitigation Strategy (REMS) called the Entereg Access Support and Education (EASE) program; hospitals must be enrolled, and the drug cannot be dispensed after discharge. Empirical formula: C25H32N2O4·2H2O, molecular weight 460.6. At physiological pH, alvimopan is zwitterionic, contributing to low solubility. It does not interact with cytochrome P450 enzymes (in vitro data); co‑administration does not alter the pharmacokinetics of intravenous morphine. No head‑to‑head trials with other agents (metoclopramide, erythromycin, methylnaltrexone) are available. The average wholesale price for a full course (15 doses) is about $1,125 [1].

C25H36N2O6

460.57

460.257

C, 65.20; H, 7.88; N, 6.08; O, 20.84

170098-38-1

Alvimopan; 156053-89-3; Alvimopan monohydrate; 1383577-62-5

5488547

White to off-white solid powder

1.166g/cm3

684.1ºC at 760mmHg

210-213ºC

367.5ºC

1.18E-19mmHg at 25°C

1.572

3.251

5

7

8

33

606

3

O([H])C1=C([H])C([H])=C([H])C(=C1[H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])N(C([H])([H])[C@@]([H])(C(N([H])C([H])([H])C(=O)O[H])=O)C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])[C@]1([H])C([H])([H])[H].O([H])[H].O([H])[H]

USPVLEIQIUNQGE-DBFLIVQGSA-N

InChI=1S/C25H32N2O4.2H2O/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19;;/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30);2*1H2/t18-,20-,25+;;/m0../s1

2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl]amino]acetic acid;dihydrate

LY246736 dihydrate; LY246736; LY-246736; HSDB 7704; HSDB7704 dihydrate; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698 dihydrate; Alvimopan dihydrate. Brand name: Entereg.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)