Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers

Little is known about the course of the plasma concentration and the bioavailability of non-steroidal anti-inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i. m. applications and regarding their plasma concentration-time course. Twenty-four healthy human volunteers were treated using a parallel group design (n = 12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by eight consecutive dermal patches every 12 hr to reach steady-state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, C-max was 0.81 +/- 0.11 (mean +/- S. E. M.) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3 +/- 3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72 +/- 0.32 ng/mL for diclofenac and 48.7 +/- 6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i. m. applications were 0.22 +/- 0.04% for diclofenac and 1.15 +/- 0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i. m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC50 values for COX-1 and COX-2, explaining the absence of dose-dependent toxicities.