Meissner Konrad, Olofsen Erik, Dahan Albert, Kharasch Evan D
Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Göttingen, Germany; Department of Anaesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Anaesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Br J Anaesth. 2025 Feb;134(2):358-367. doi: 10.1016/j.bja.2024.08.042. Epub 2024 Nov 26.
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.
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.
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).
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.
吗啡和氢吗啡酮在起效时间、作用强度及持续时间和副作用方面存在差异。阿片类药物在药代动力学和药效动力学的个体间变异性差异可能会影响合理的药物选择。交叉药物研究比平行组研究能提供更丰富的个体间变异性数据。利用健康志愿者静脉注射吗啡和氢吗啡酮交叉研究的数据，我们检验了吗啡和氢吗啡酮在个体间药代动力学变异性方面存在差异的假设。
对51名志愿者进行随机交叉研究，他们分别在相隔1 - 2周的时间接受2小时的氢吗啡酮（0.05或0.1毫克/千克静脉注射）或吗啡（总量0.1或0.2毫克/千克静脉注射）输注，采用三室模型评估母体阿片类药物及结合葡糖醛酸的动脉阿片类药物和代谢物浓度，并使用群体建模（NONMEM）。主要结局是基于个体模型参数变异系数（%CV）的药代动力学个体间变异性，其计算方式为√[exp(ω)-1]×100，其中ω为个体间变异性。
对每种药物以及吗啡 - 氢吗啡酮联合模型进行数据分析。两种分析均表明，氢吗啡酮和吗啡的个体间变异性相当，结构模型参数的%CV范围为9%至31%（联合分析）。同样，吗啡和氢吗啡酮的加性和相对残差误差具有相当的变异性，分别为20 - 40%和72 - 87%（联合分析）。
吗啡和氢吗啡酮在个体间药代动力学变异性方面无统计学显著差异或临床意义上的差异。在这两种阿片类药物之间进行选择时，个体间药代动力学变异性似乎并非一个有意义的考虑因素。
