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Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model

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Abstract

Purpose. Population pharmacokinetics of a fast release diclofenac wereassessed with special focus on pharmacodynamic implications.

Methods In a double blind four-way crossover study, 20 healthyvolunteers received orally 50 and 100 mg diclofenac-Na effervescent(“fast-release NSAID”), 50 mg diclofenac tablets (“control”), or placebo.Population pharmacokinetics of the fast release diclofenac wereassessed using a nonlinear mixed effects modeling approach(NON-MEM). Analgesic effects were investigated by means of anexperimental pain model based on both pain-ratings and cortical evoked potentialsafter specific stimulation of nasal nociceptors with short pulses ofgaseous CO2.

Results. Pharmacokinetics of fast release diclofenac were bestdescribed by a two-compartment population model, with an estimatedterminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tabletswere highly variable and a population pharmacokinetic model couldnot be obtained. As an indication of an early onset of analgesic effects,100 mg fast release diclofenac but not the tablets significantly reducedthe amplitudes of pain-related evoked potentials at 30 min afteradministration.

Conclusions. Earlier drug absorption and lower pharmacokineticvariability of the fast-release formulation are likely to be preserved ina population.

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Authors and Affiliations

  1. Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5640

    Jörn Lötsch

  2. Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Fahrstr. 17, D-91054, Erlangen, Germany

    Birgit Kettenmann, Bertold Renner, Kay Brune & Gerd Kobal

  3. Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5640

    David Drover

  4. Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany

    Gerd Geisslinger

Authors
  1. Jörn Lötsch
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  2. Birgit Kettenmann
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  7. Gerd Kobal
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Lötsch, J., Kettenmann, B., Renner, B. et al. Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model. Pharm Res 17, 77–84 (2000). https://doi.org/10.1023/A:1007574710140

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