Alvimopan, a mu-
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.