Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers.
To investigate the pharmacokinetics of naloxone in healthy volunteers, we undertook an open-label crossover study in which six male volunteers received naloxone on five occasions: intravenous (0.8 mg), intramuscular (0.8 mg), intranasal (0.8 mg), intravenous (2 mg), and intranasal (2 mg). Samples were collected for 4 hours after administration for 128 samples in total. A population pharmacokinetic analysis was undertaken using NONMEM. The data were best described by a three-compartment model with first-order absorption for intramuscular and intranasal administration, between-subject variability on clearance and central volume, lean body weight on clearance, and weight on central volume. Relative bioavailability of intramuscular and intranasal naloxone was 36% and 4%, respectively. The final parameter estimates were clearance, 91 L/hr; central volume, 2.87 L; first peripheral compartment volume, 1.49 L, second peripheral compartment volume, 33.6 L; first intercompartmental clearance, 5.66 L/hr; second intercompartmental clearance, 29.8 L/hr; Ka (intramuscular), 0.65; and Ka (intranasal), 1.52. Median time to peak concentration for intramuscular naloxone was 12 minutes and for intranasal, 6 to 9 minutes. A combination of intravenous and intramuscular naloxone provided immediate high and then detectable concentrations for 4 hours. Intranasal naloxone had poor bioavailability compared with intramuscular. Combined intravenous and intramuscular administration may be a useful alternative to naloxone infusions.
Dowling
Jonathonm
J
Clinical and Experimental Toxicology Unit, Prince of Wales Hospital and Prince of Wales Clinical School, University of NSW, Sydney, Australia.
Isbister
Geoffrey K
GK
Kirkpatrick
Carl M J
CM
Naidoo
Daya
D
Graudins
Andis
A
D000281:Administration, Intranasal; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009270:Naloxone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
D009292:Narcotic Antagonists; D009270:Naloxone