Alvimopan pharmacokinetics (PK) & pharmacodynamics (PD) in patients with chronic constipation (CC)

Background To characterize the PK/PD of alvimopan and its active metabolite (ADL 08–0011) in CC patients. Method Twenty females/three males with CC received placebo or 3 mg alvimopan (a peripherally-acting μ-opioid antagonist) BID for 7 days in a double-blind, randomized, crossover study. The PK of alvimopan & metabolite were characterized. Whole bowel transit (WBT) & mean colonic transit time (MCTT) were determined. Total bowel movements (BM) & spontaneous complete BM (SCBM) were recorded. Safety was monitored. PD assessments were reported previously.a Results The geometric mean steady-state (SS) AUCτ, Cmax, & Cmin of alvimopan were 10.7 ng*hr/mL, 2.1 ng/mL, & 0.3 ng/mL, respectively. Metabolite concentrations were variable. Metabolite concentrations were at steady-state (SS) in ~50% of subjects on day 6 and were higher in patients that were at SS than those not at SS (AUC12= 98 and 48 hr*ng/mL, respectively). The relationship between concentrations of alvimopan or metabolite and response (WBT, MCTT, BM or SCBM) was explored. Simulations were used to predict doses to be used in further clinical trials. Conclusion Alvimopan PK in CC patients was similar to healthy volunteers, although Cmin was higher in CC patients. Metabolite concentrations were variable, but were in the range of those predicted. The relative contribution of plasma concentrations of parent and metabolite to activity remains unclear in CC. Clinical Pharmacology & Therapeutics (2005) 77, P49–P49; doi: 10.1016/j.clpt.2004.12.080