THE EFFECT OF RENAL-INSUFFICIENCY AND HEMODIALYSIS ON THE PHARMACOKINETICS OF NALMEFENE

The disposition of nalmefene, an opioid antagonist intended for the re versal of opioid-induced respiratory depression, and its primary metab olite nalmefene glucuronide, were characterized in adult volunteers wi th normal renal function and in patients with endstage renal disease ( ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal rena l function received a single intravenous dose of 2 mg, and patients wi th ESRD received two separate doses of 1 mg nalmefene hydrochloride. T erminal elimination half-life (t1/2) of both nalmefene and nalmefene g lucuronide was prolonged in patients with ESRD compared with that in p articipants with normal renal function. The steady-state volume of dis tribution (Vd(ss)) of nalmefene was significantly higher and total bod y clearance lower in patients with ESRD than in participants with norm al renal function. Hemodialysis clearance of nalmefene was approximate ly 3.3% of total body clearance, Although the hemodialysis clearance o f nalmefene glucuronide was 179.3 +/- 24.1 mL/min and its t1/2 was sig nificantly reduced during dialysis to 5.2 +/- 2.3 hours, a dramatic re bound of nalmefene glucuronide concentrations of 75.7% was observed 7. 7 +/- 5.4 hours after the end of hemodialysis. Thus, hemodialysis does not result in clinically significant alterations in the disposition o f nalmefene or its primary metabolite, nalmefene glucuronide. These da ta suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be admini stered less frequently due to the prolonged elimination of the active moiety, nalmefene.