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Pharmacokinetic-pharmacodynamic modeling of the miotic effects of dihydrocodeine in humans.

Author(s): Schmidt H, Lotsch J

Affiliation(s): Pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.

Publication date & source: 2007-11, Eur J Clin Pharmacol., 63(11):1045-54. Epub 2007 Sep 5.

Publication type: Randomized Controlled Trial

AIM: The purpose of this study was to evaluate the pharmacokinetic-pharmacodynamic interrelations of pupillary effects of dihydrocodeine by two different analytic approaches. METHODS: Dihydrocodeine plasma concentrations and miotic effects were available from a previous study with 24-h measurements after administration of 60 mg dihydrocodeine to nine healthy young men. Plasma concentration versus time course was described either by a one-compartment model or by linear splines using NONMEM. Dihydrocodeine concentrations at the effect site were obtained by convolution of a first-order transfer function with the function describing the plasma concentration versus time courses, and miotic effects were related to effect-site concentrations by a sigmoidal pharmacodynamic model. RESULTS: Bayesian individual fits of miotic effects were only slightly better with the spline approach than with the compartmental approach (median individual absolute weighted residuals 0.046 versus 0.058, respectively, Wilcoxon test p = 0.008; residual errors of an additive error model 0.0979 versus 0.184, respectively). Both approaches provided similar pharmacokinetic-pharmacodynamic population parameter values. The transfer half-life between plasma and effect site was 21.1 min (95% CI 11.1-34.7 min) and 19.8 min (95% CI 11.9-34 min) with spline and compartmental approaches, respectively, and miosis occurred with EC50 of 207 or 230 ng/ml, respectively. CONCLUSION: Two modeling approaches to the miotic effects of dihydrocodeine provided similar transfer half-lives between plasma and effect site, which also agreed with previous independently estimated values obtained from analgesic effects, suggesting that pupil size is a valid biomarker to estimate the value of ke0 for opioid central nervous system (CNS) effects.

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