Two Phase I, Randomized, Open-Label, Multiple-Dose, Crossover Studies Investigating the Systemic Bioavailability of...

Topical diclofenac diethylamine (DDEA) gels relieve pain while maintaining low diclofenac systemic concentrations in nontarget tissues. Characterizing diclofenac systemic exposure remains a mandated element in the development of topical diclofenac products. Two Phase I, randomized, open-label, multiple-dose, crossover studies were conducted with the objective of assessing the systemic bioavailability of DDEA topical gels and oral diclofenac tablets in healthy volunteers. In addition to evaluating bioavailability, safety and tolerability were also examined. In Study 1, participants applied DDEA 2.32% gel twice daily (with/without semiocclusive bandage) or DDEA 1.16% gel 4 times daily (no bandage) to 1 ankle. In Study 2, participants applied DDEA 2.32% gel twice daily to 1 knee or both knees. Both studies compared topical treatments with oral diclofenac sodium tablets 50 mg 3 times daily. In Study 1, similar diclofenac bioavailabilities were observed for DDEA 1.16% gel 4 times daily and DDEA 2.32% gel twice daily; the presence of a semiocclusive bandage had a minimal impact on bioavailability. In Study 2, diclofenac bioavailability was proportional to the number of DDEA 2.32% gel application sites. Systemic diclofenac concentration for topical application was significantly lower (up to 150- and 75-fold) compared to oral treatments and was well tolerated. These studies contribute to the benefit-risk assessment of topical DDEA.