Safety and efficacy update: Alvimopan in postoperative ileus

Abstract

Postoperative ileus (POI) in patients undergoing abdominal surgery is associated with signifi cant morbidity. In 2008, alvimopan (Entereg ® ) was approved by the Food and Drug Administration (FDA), and is the only available POI therapy in the United States for patients undergoing bowel resection. Data from preclinical studies demonstrate that alvimopan and its primary metabolite, ADL 08-0011, behave as potent μ opioid receptor antagonists. In animals, alvimopan and ADL 08-0011 attenuate opioid agonist-induced reductions in gastrointestinal (GI) transit. Higher doses of alvimopan are required to inhibit opioid-induced analgesia as a result of its inability to penetrate the central nervous system (CNS). ADL 08-0011 is also peripherally selective, although to a lesser degree than alvimopan. In multiple species, including humans, alvimopan has low oral bioavailability, while ADL 08-0011, following its generation by human gut microfl ora, is more readily absorbed and achieves higher exposures. Three Phase 2 and fi ve Phase 3 clinical trials have been conducted to investigate the effi cacy and tolerability of alvimopan in patients undergoing bowel resection. An additional Phase 3 study was conducted in hysterectomy patients. In the majority of the studies, statistically signifi cant, and clinically meaningful, acceleration of GI recovery has been demonstrated. Consistent with animal data, alvimopan has no effect on opioid agonist-induced analgesia in healthy human subjects and POI patients. Clinical experience to date in POI patients indicates that alvimopan is well tolerated when used according to its approved dosing regimen (12 mg b.i.d. for up to 7 days). In this article, the preclinical and clinical properties of alvimopan are reviewed.

The effects of ulimorelin, a ghrelin agonist, on liquid gastric emptying and colonic transit in humans

“…POI is primarily a lower GI disorder, as reflected by the relatively greater delay in the recovery of the colon compared to the stomach and small intestine after laparotomy. 16,17 In prior POI trials, the dual primary endpoint was the time to intake of solid food and time to first bowel movement. Since the colon recovers last, time to first bowel movement occurs later, gating the primary endpoint.…”

“…Combined with the results of a previous study of another ghrelin agonist, relamorelin, in healthy volunteers, we conclude that the effects of ghrelin in humans are predominantly in the upper GI tract, with minimal effects on colonic transit. POI is primarily a lower GI disorder, as reflected by the relatively greater delay in the recovery of the colon compared to the stomach and small intestine after laparotomy . In prior POI trials, the dual primary endpoint was the time to intake of solid food and time to first bowel movement.…”

“…Although POI represents diffuse disruption of motility in the stomach, small intestine, and colon, the disruption of colonic motility is greater than other organs and recovers last . A recent study of another peptide ghrelin agonist, relamorelin, suggested little effect on colonic transit, despite the reported 3‐fold greater potency than ghrelin …”

“…[13][14][15] Although POI represents diffuse disruption of motility in the stomach, small intestine, and colon, the disruption of colonic motility is greater than other organs and recovers last. 16,17 A recent study of another peptide ghrelin agonist, relamorelin, suggested little effect on colonic transit, despite the reported 3-fold greater potency than ghrelin. 18 Ulimorelin is more than 99% bound to α-1 acid glycoprotein (AAGP), an acute phase reactant in plasma 19 ; free ulimorelin, the active moiety, is therefore approximately 100-fold lower in concentration than total drug.…”

Effect of ICU interventions on gastrointestinal motility

“…Although data on safety and efficacy of traditionally used opioid antagonists (naloxone and nalbuphine) are not satisfactory, a recent publication [34 ] underlines the impact of alvimopan (Entereg; Adolor Corporation, Exton, Pennsylvania, USA) and methylnaltrexone (Relistor; Wyeth/Pfizer Inc., New York, New York, USA). Both substances are highly selective peripheral m-receptor antagonists and have the potential to reverse opioid-induced gastrointestinal side effects [35,36]. Concerning Entereg (Adolor Corporation), a recently published study [37] failed to reproduce the positive effects of this substance on intestinal function, unless patients were treated with i.v.…”