Systemic Bioavailability of Topical Diclofenac: Sodium 1% Versus Diethylamine 1.16% and the Effect of Heat or Exercise in a Randomized Cross‐Over Study

Abstract Diclofenac is a widely used topical nonsteroidal anti‐inflammatory drug (NSAID) for pain and inflammation. This study evaluated the relative bioavailability of diclofenac from diclofenac sodium (DS) gel 1% versus diclofenac diethylamine (DEA) gel 1.16% and assessed whether adjunct heat or moderate exercise influences systemic absorption of diclofenac from DS gel 1%. General and local tolerability of DS gel 1% was also examined. Thirty‐six adults aged ≥50 years were enrolled in a single‐center, open‐label, randomized, two‐arm, three‐way crossover study consisting of three 7‐day treatment periods separated by 14‐day washouts. Each sequence included DS gel 1%, DEA gel 1.16%, and DS gel 1% combined with either heat (one arm) or moderate exercise (other arm). Treatments were applied four times daily. Plasma diclofenac levels and 24‐h urine samples were collected on Days 1 and 7 using a validated LC‐MS/MS assay. Systemic exposure (AUC 0–24 ) of DEA gel versus DS gel was comparable (GMR 90.7%; 90% CI: 82.7–99.5). Heat resulted in an excursion of the lower bound of the AUC 0 ‐ 24 90% confidence interval below the standard lower bioequivalence bound of 80% (GMR 92.5%; 90% CI: 77.3–111.0), while exercise showed no meaningful effect (GMR 103%; 90% CI: 87.8–120.0). As expected, given similar plasma exposure between treatments, urinary excretion was also similar (∼0.5% of the administered dose), supporting comparable systemic disposition.