Alvimopan

Alvimopan

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Alvimopan is a drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

 which behaves as a peripherally acting μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 antagonist. With limited ability to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

, many of the undesirable side-effects of the opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 agonists such as constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

 are minimized without affecting analgesia or precipitating withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...

s. The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 reviewed the safety and efficacy data for alvimopan and approved its use in May 2008.

Indication


Alvimopan is indicated in patients to avoid postoperative ileus following partial large or small bowel resection with primary anastomosis. Alvimopan accelerates the gastrointestinal recovery period as defined by time to first bowel movement or flatus.

Mechanism of action


Alvimopan competitively binds to mu-opioid receptor in the gastrointestinal tract. Unlike methylnaltrexone
Methylnaltrexone
Methylnaltrexone is one of the newer agents of peripherally-acting μ-opioid antagonists that act to reverse some of the side effects of opioid drugs such as constipation without affecting analgesia or precipitating withdrawals...

 (another peripherally acting mu-receptor antagonist) that bears a quaternary amine, alvimopan owes its selectivity for peripheral receptors to its kinetics. Alvimopan binds to peripheral mu-receptors with a Ki of 0.2 ng/mL and dissociates slower than most other ligands.

Absorption


Peak plasma concentration (Cmax) of alvimopan is reached approximately 2 hours after oral dosing, while the Cmax for metabolite occurs 36 hours after an oral dose. Alvimopan's high affinity for the peripheral mu-receptor results in an absolute bioavailability less than 7%.

Distribution


80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.

Metabolism


Alvimopan undergoes no significant hepatic metabolism, but is metabolized by intestinal flora. Gut metabolism produces an active metabolite with no clinically significant contribution to drug effect.

Elimination


Alvimopan undergoes 35% renal excretion and greater than 50% biliary excretion. Drug metabolized by intestinal flora is excreted in the feces. Alvimopan's half-life of elimination is 10 to 17 hours, while that of the gut metabolite is 10 to 18 hours.

Dosing and administration


Alvimopan is only approved for short term use of no more than 15 doses. It is available on an inpatient basis at institutions approved by and registered with the Entereg Access Support and Education (E.A.S.E.) program. The drug is a 12 mg blue hard gelatin capsule. The recommended adult dose is to administer 12 mg 30 minutes to 5 hours preoperatively and 12 mg twice daily for seven days postoperatively. A patient should receive no more than 15 doses.

Adverse effects


The most common side effects associated with alvimopan are:
Adverse Effect Frequency (%) with placebo Frequency (%) with alvimpoan
Dyspepsia 4.6 7.0
Hypokalemia 8.5 9.5
Back Pain 1.7 3.3
Delayed Micturition 2.1 3.2

Contraindications


Alvimopan is absolutely contraindicated in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately prior to when alvimopan would be initiated because individuals with recent exposure to opioids are expect to be more sensitive to the effects of mu-opioid receptor antagonists. The peripheral site of action of alvimopan suggests that such a heightened sensitivity would precipitate gastrointestinal effects beyond dyspepsia.

Myocardial infarction


During clinical trials, a 12 month study of alvimopan dosed at 0.5 mg twice daily reported observed more myocardial infarction in the treatment group compared to placebo. The majority of these events occurred between months one and four of treatment. No causal relationship between alvimopan and myocardial infarction was ever established, and this effect has not been reproduced in subsequent studies.

Severe hepatic impairment


During clinical trials, one patient with severe hepatic impairment appreciated a 10-fold increase in Cmax compared to healthy volunteers. Two other patients with a similar Child-Pugh score (class C) did not experience this same phenomenon.

End-stage renal disease


Alvimopan has not been studied in patients with end-stage renal disease.

Bowel obstruction


It is not recommended to use alvimopan in surgical candidates for correction of a complete bowel obstruction.

Drug interactions


Alvimopan is not substrate for the cytochrome P450 enzyme system. Therefore, no interactions are expected with hepatically metabolized drugs. Alvimopan is substrate for p-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...

. Expect interactions with known p-glycoprotein inhibitors such as amiodarone, depridil, diltiazem, cyclosporine, itraconazole, quinine, quinidine, spironolactone, and verapamil.