1. ¹AdolorCorporation, Exton, Pennsylvania, USA
2. ²"P Less Than" Company, San Francisco, California, USA
3. ³Clinical Pharmacokinetics/Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina, USA

Correspondence: JF Foss, (fossj@ccf.org)

Received 18 April 2007; Accepted 6 June 2007; Published online 25 July 2007.

Abstract

Alvimopan, a -opioid antagonist without anti-analgesic effects, is being developed to manage postoperative ileus. We characterized the population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.