Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers

Abstract

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 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 IC values for COX-1 and COX-2, explaining the absence of dose-dependent toxicities.

Optimization and Evaluation of the In Vitro Permeation Parameters of Topical Products with Non-Steroidal Anti-Inflammatory Drugs through Strat-M® Membrane

“…The drug was specifically designed to meet topical anti-inflammatory treatment requirements, such as adequate anti-inflammatory and analgesic efficacy, good local and systemic tolerability, and good transcutaneous penetrating ability [ 32 ]. It is rapidly metabolized to flufenamic acid in vivo, which has similar properties as the parent drug [ 57 ].…”

Incidence of postoperative atrial fibrillation in transdermal β-blocker patch users is lower than that in oral β-blocker users after cardiac and/or thoracic aortic surgery

“…(2) A transdermal patch can be easily removed if hypotension or bradycardia occurs. Although the blood level of a transdermal patch can be sustained after removal, it may be possible to remove the patch before the blood concentration reaches the maximum blood level as the absorption of β-blocker in patients with the patch is slower compared with oral type [9,24]. 3Heart failure-induced edema of the intestines can block the gastrointestinal absorption of orally administered β-blockers.…”

A wireless smart patch for the controlled repetitive transdermal administration of therapeutic agents

“…At temperatures approaching 45 °C, the wax transitions from solid to liquid. Diclofenac was used as the model drug given its analgesic properties and the fact that there are commercial diclofenac transdermal patches already available [16,17]. It is also extensively used as a model in the development of transdermal patch systems -those relying on purely passive transfer [22][23][24] and those exploiting physical enhancement such as heat or iontophoresis [25].…”

“…Transdermal delivery avoids many of the harmful side effects associated with oral ingestion and gastrointestinal irritation and as first pass hepatic degradation is bypassed, lower dosage of drugs is possible. The success of the delivery strategy is evidenced in part by the availability of numerous commercial products ranging from over the counter (OTC) nicotine [9,10] patches through to prescription medicines such as estradiol [11], fentanyl [12,13], rivastigmine [14], rotigotine [15] and diclofenac [16,17] covering hormone replacement therapy, chronic pain, dementia, Parkinson's disease and acute pain respectively. The commercialisation of transdermal drug patches has been progressing since 1979 and, while the nature of the therapeutic agent and entrapment matrices can vary widely, the underlying mechanism has remained relatively unchanged.…”