David T. Beattie

Department of Pharmacology, Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, U.S.A.

Abstract

Postoperative ileus (POI) in patients undergoing abdominal surgery is associated with significant 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 microflora, is more readily absorbed and achieves higher exposures. Three Phase 2 and five Phase 3 clinical trials have been conducted to investigate the efficacy 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 significant, 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.

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