Morphine and hydromorphone pharmacokinetics in human volunteers: population-based modelling of interindividual and opioid-related variability.

Background: Morphine and hydromorphone have differing onsets, magnitudes, and durations of effects and side-effects. Differences between opioids in their interindividual variabilities in pharmacokinetics and pharmacodynamics might influence rational drug selection. Crossover drug studies can provide more informative interindividual variability data than parallel group studies. Using data from a crossover study of i.v. morphine and hydromorphone in healthy volunteers, we tested the hypothesis that morphine and hydromorphone differ in their interindividual pharmacokinetic variability.

Methods: Arterial opioid and metabolite concentrations from a randomised crossover study in 51 volunteers receiving a 2-h infusion of hydromorphone (0.05 or 0.1 mg kg i.v.) or morphine (total 0.1 or 0.2 mg kg i.v.) 1-2 weeks apart were evaluated with a three-compartmental model for parent opioid and incorporating glucuronides using population modelling (NONMEM). The primary outcome was interindividual variability in pharmacokinetics, based on the coefficient of variation (%CV) of individual model parameters, calculated as √[exp(ω)-1]×100 where ω is the interindividual variability.

Results: Data were analysed per drug and in a combined morphine-hydromorphone model. Both analyses indicate that interindividual variabilities for hydromorphone and morphine were comparable with %CV ranging from 9% to 31% for structural model parameters (combined analysis). Similarly, additive and relative residual errors had comparable variabilities, 20-40% and 72-87%, respectively, for morphine and hydromorphone (combined analysis).

Conclusions: Morphine and hydromorphone did not differ in a statistically significant or clinically meaningful manner in their interindividual pharmacokinetic variability. Interindividual pharmacokinetic variability does not appear a meaningful consideration in the choice between these two opioids.