Single and multiple dose pharmacokinetics of long-acting injectable naltrexone

Abstract

Background Long-acting naltrexone (LA-NTX) is an injectable microsphere formulation being developed to achieve continuous naltrexone (NTX) exposure for 1 month in the treatment of alcohol dependence. Methods This was a single center, randomized, double-blind, placebo-controlled, parallel design study in healthy subjects (n=42) to evaluate the PK of LA-NTX following single (190mg; 380mg) and multiple (380mg; q28d) IM doses vs. oral naltrexone (50mg; qd). PK parameters for NTX and its primary metabolite, 6β-naltrexol (6β-NOH) were calculated by noncompartmental methods. Results Mean NTX concentrations were >1 ng/mL over 28 days following LA-NTX 380mg; 6β-NOH concentrations were greater than, but parallel to, NTX. Tmax was ~2–3 and t1/2 was ~5–7 days for NTX and 6β-NOH. NTX AUC0-∞ following LA-NTX 380mg (144±30 ng*days/mL) was 2-fold greater than following LA-NTX 190mg (72±9 ng*days/mL). Multiple dose PK was predicted by single dose; steady state was reached with the second LA-NTX 380mg dose. NTX and 6β-NOH accumulation was ≤13%. NTX AUC0–28d was 4-fold greater following LA-NTX 380mg (160 ng*days/mL) vs. oral 50mg daily (~41 ng*days/mL; dose=1400mg/28 days); 6β-NOH AUC0–28d (294 ng*days/mL) was 70% lower vs. oral (1002 ng*days/mL). Conclusions Single dose PK of LA-NTX was dose proportional and predicted steady state observations. LA-NTX provided greater exposure and less fluctuation in NTX concentrations over a 28 day period, with a lower overall dose, compared to daily oral administration. Clinical Pharmacology & Therapeutics (2005) 77, P42–P42; doi: 10.1016/j.clpt.2004.12.053