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 were asse ssed with special focus on pharmacodynamic implications. Methods. In a double blind four-way crossover study, 20 healthy volunteers received orally 50 and 100 mg diclofenac-Na effervescent ("fast release NSA ID"), 50 mg diclofenac tablets ("control"), or placebo. Population pharmaco kinetics of the fast release diclofenac were assessed using a nonlinear mix ed effects modeling approach (NON-MEM). Analgesic effects were investigated by means of an experimental pain model based on both pain-ratings and cort ical evoked potentials after specific stimulation of nasal nociceptors with short pulses of gaseous CO2. Results. Pharmacokinetics of fast release diclofenac were best described by a two-compartment population model, with an estimated terminal half-life o f 1.2 hours. Pharmacokinetics of diclofenac tablets were highly variable an d a population pharmacokinetic model could not be obtained. As an indicatio n of an early onset of analgesic effects, 100 mg fast release diclofenac bu t not the tablets significantly reduced the amplitudes of pain-related evok ed potentials at 30 min after administration. Conclusions, Earlier drug absorption and lower pharmacokinetic variability of the fast-release formulation are likely to be preserved in a population.