The effect of renal insufficiency and hemodialysis on the pharmacokinetics of nalmefene.
The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid-induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end-stage renal disease (ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal renal function received a single intravenous dose of 2 mg, and patients with ESRD received two separate doses of 1 mg nalmefene hydrochloride. Terminal elimination half-life (t1/2) of both nalmefene and nalmefene glucuronide was prolonged in patients with ESRD compared with that in participants with normal renal function. The steady-state volume of distribution (Vdss) of nalmefene was significantly higher and total body clearance lower in patients with ESRD than in participants with normal renal function. Hemodialysis clearance of nalmefene was approximately 3.3% of total body clearance. Although the hemodialysis clearance of nalmefene glucuronide was 179.3 +/- 24.1 mL/min and its t1/2 was significantly reduced during dialysis to 5.2 +/- 2.3 hours, a dramatic rebound 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 of nalmefene or its primary metabolite, nalmefene glucuronide. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be administered less frequently due to the prolonged elimination of the active moiety, nalmefene.
Matzke
G R
GR
Department of Pharmacy and Therapeutics, University of Pittsburgh, Pennsylvania 15261, USA.
Frye
R F
RF
Alexander
A C
AC
Reynolds
R
R
Dixon
R
R
Johnston
J
J
Rault
R M
RM
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D006435:Renal Dialysis
D005965:Glucuronates; D009292:Narcotic Antagonists; D009271:Naltrexone; C038981:nalmefene