Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.
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.
Foss
J F
JF
AdolorCorporation, Exton, Pennsylvania, USA. fossj@ccf.org
Fisher
D M
DM
Schmith
V D
VD
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001682:Biological Availability; D005215:Fasting / Q000097:blood / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013514:Surgical Procedures, Operative
D010880:Piperidines; D017450:Receptors, Opioid, mu; C419502:alvimopan