Alvimopan (entereg?), a novel opioid antagonist, achieves active systemic concentrations

Background Alvimopan is a potent (Ki 0.4 nM), selective, peripherally-acting mu-opioid antagonist under investigation for the management of opioid-induced side effects such as post-operative ileus and opioid-induced bowel dysfunction. It has a low bioavailability of 6%. The aim was to establish the plasma concentrations of alvimopan and their relation to potential active levels. Methods With IRB approval, subjects of both genders >18 yoa (8/group; double blind) were given placebo, 6, 12, 18, or 24 mg of alvimopan po on day 1 and then BID for 9 doses starting on Day 2. Plasma was analyzed (HPLC/MS/MS) after the first dose, at daily trough, and for 120 hrs after the last dose. Non-compartmental methods were used to calculate Cmax, Tmax, t1/2, AUC, at Single Dose (SD) and Steady State (SS), accumulation index (AI), Cavg, Cmin, and fluctuation (SS only) and urinary excretion (Ae, CLR, and % excreted) for alvimopan and its metabolite (SS only). Results 40 subjects completed the study. Mean PK for alvimopan were linear from 6–18 mg. SD Cmax was 5.07–15.88 ng/ml, AUC was 17.7–54.6 hr*ng/mL, and t1/2 was 2.4–5.5 hrs. Values were similar at SS. No accumulation was evident. Plasma concentrations of the metabolite were generally higher, more variable and had not achieved SS. Conclusions Single and multiple po doses of alvimopan up to 18 mg produce linear PK with Cmax values exceeding the Ki for opioid receptor binding. This supports a potential for systemically mediated activity of alvimopan on the side effects of opioids. Clinical Pharmacology & Therapeutics (2005) 77, P74–P74; doi: 10.1016/j.clpt.2004.12.175