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

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.