Clinical pharmacokinetics of transdermal absorption of diclofenac diethylammonium plaster in healthy volunteers

Background: Transdermal absorption pharmacokinetics of diclofenac diethylammonium(DEA) plaster (Rheumastop®) were estimated after single and multiple application in normal healthy subjects. Methods: Single plaster of 120 mg diclofenac DEA was applied to upper arm of 14 healthy male subjects for 24 hours and replaced with new plaster every 24 hours for following 14 days. Serial blood samples were drawn after the first dose and the last dose of the plaster and intermittent blood samples were drawn at 3, 5, 7 and 10 days of the study. Diclofenac concentrations in plasma, urine and plaster were determined by high performance liquid chromatography method. Pharmacokinetic parameters were estimated by both noncompartmental analysis and compartmental analysis of 2-compartment, 2-segment simultaneous input model with using NONMEM®. Results: The amount of diclofenac absorbed during 24 hour application of each diclofenac DEA plaster was estimated to 6.6 ± 3.5 mg and was corresponded to 6.9 % of total amount of diclofenac measured in the intact plaster (average 95.17 mg). After the first dose of a diclofenac plaster, the average peak plasma concentration was reached to maximum concentration (7.4 ± 3.6 ng/ml) at 12.4 ± 9.2 hour. After multiple doses of diclofenac DEA plaster, the plasma concentration reached to peak level (15.9 ± 11.7 ng/ml) at 7.9 ± 7.4 hours, then concentrations were declined very slowly to 10.0 ± 5.1 ng/ml at the time of next application. The mean AUC of diclofenac at steady state was estimated to 273 ± 205 ng/ml · h. From the compartmental model for the transdermal absorption of diclofenac DEA plaster, 75 ± 14 % of diclofenac dose was described by the burst zero order input model and the remained was by slow first order input model. The estimated volume of distribution (Vd/F) was estimated to 2.2 ± 0.8 L/kg and half life was 3.4 ± 0.8 hour. Conclusions: The diclofenac DEA plaster which shows initial burst and slow continuous input absorption kinetics appears to be able to maintain constant plasma level during 24 hour application. The measured plasma concentration-time profiles at steady-state are expected to be adequate for therapeutic effect, taking into account the comparable results to those from twice a day application of 185 mg diclofenac HEP plaster of which clinical effect has been well established. However, further clinical trials in patients are remained to document the clinical effects of this new diclofenac plaster.