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.