Population pharmacokinetics of heroin and its major metabolites

In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug.

To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined.

Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The 'chasing the dragon' technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450 mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling.

The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p < 0.05). No other significant relationships between covariates and pharmacokinetic parameters were discovered.

Pharmacokinetic parameters of heroin and its five major metabolites were assessed simultaneously in one integrated model. Covariate analyses revealed that sex, bodyweight, benzodiazepine use and creatinine clearance (>60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependency.