Introducing an In Vivo Protocol to Evaluate Skin Penetration of Topical Drugs: Proof-of-Concept with Naproxen in Humans

Abstract

Background. Current clinical guidelines recommend the use of topical nonsteroidal antiinflammatory drugs (NSAIDs), such as naproxen, to treat hand and knee osteoarthritis and other musculoskeletal disorders. However, detailed insights into naproxen's cutaneous pharmacokinetics remain underexplored. Aim. This study aims to provide quantitative in vivo evidence that naproxen skin penetration follows Fick's law of diffusion. In addition, it seeks to explore whether the penetration profile is compatible with localized presystemic retention, which could improve therapeutic efficacy and limit systemic exposure. Methods. Five healthy volunteers participated in this proof-of-concept study. A commercially available 5.5\% naproxen sodium gel was applied to the volar surface of the forearm, and naproxen penetration kinetics were determined. The naproxen penetration versus time profiles were fitted to a mathematical model assuming Fick's law of diffusion, and the model's predictive performance was evaluated. Results. Naproxen skin penetration increased during the first 4 h reaching a plateau that indicated equilibrium was achieved and a presystemic drug reservoir was formed, limiting systemic exposure. The experimental data were adequately fitted by a mathematical model based on Fick's law of diffusion. Maximal naproxen release (M infinity), expressed as a percentage of the actually applied dose, was 23.85 +/- 1.81\%. The penetration rate constant ( k ) was 0.73 +/- 0.18 h-1 , and the penetration half-life ( t1/2 ) was 0.99 +/- 0.21 h. Conclusion. This study demonstrates that topical naproxen follows predictable Fickian kinetics and shows a potential tissue-level reservoir after penetration. This supports its use as a safe and effective topical agent for localized inflammatory conditions. (c) 2026 The Authors. Published by Elsevier Inc. on behalf of Instituto Mexicano del Seguro Social (IMSS). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)