Background Topical non-steroidal anti-inflammatory drugs (NSAIDs) result in lower systemic drug levels compared to oral NSAIDs and effectively relieve pain, with good local and excellent systemic tolerability.1 Thus, there is increasing interest in topical NSAIDs; several professional societies recommend their use prior to therapy with oral NSAIDs. 2 Diclofenac diethylamine (DDEA) 2.32% gel can relieve pain for up to 12 h.3
Objectives To compare the systemic bioavailability of diclofenac following topical application of DDEA 2.32% gel (4 g per knee, twice per day) on 1 knee vs. 2 knees, and vs. oral diclofenac sodium (50 mg tablet, three times per day) in healthy volunteers representative of the OA population.
Methods In this open-label, crossover, systemic bioavailability study, 40 healthy volunteers (mean age 60 years) were enrolled to receive all three above mentioned treatments for 7 days in a randomized sequence. Pharmacokinetic data in plasma and urine and safety data were collected throughout. The study was completed by 35 subjects and data from 38 subjects was included in the analysis.
Results Steady state was reached approximately at Day 7 with topical diclofenac and at Day 2 with oral diclofenac. Application of DDEA 2.32% gel to 2 knees roughly doubled the exposure vs. application to 1 knee. Day 7 ratios for AUC, Cmax and Cmin over 0–12 h were 180%. Oral dosing vastly increased systemic exposure on Day 7 vs. topical dosing; AUC and Cmax over 0-24 h with oral diclofenac were 14-fold and 87-fold higher vs. DDEA 2.32% gel applied to 2 knees, and 27-fold and 161-fold higher vs. DDEA 2.32% gel applied to 1 knee. Correspondingly, Day 7 total urinary excretion over 24 h of diclofenac and of the 4'-OH metabolite with oral diclofenac were 22-fold and 38-fold higher vs. DDEA 2.32% gel applied to 2 knees, and 44-fold and 75-fold higher with oral diclofenac vs. DDEA 2.32% gel applied to 1 knee. Plasma levels and rates of urinary excretion of diclofenac increased over 7 days of application of DDEA 2.32% gel; the Day 7/Day 1 ratio of AUC(0-24) for DDEA 2.32% gel applied to 2 knees was 6.4. Drug-related AEs were seen in 2.6% of subjects treated with topical diclofenac (burning sensation with explanatory underlying cause) vs. 28.2% of those treated with oral diclofenac (mostly gastrointestinal related).
Conclusions Systemic exposure to diclofenac from either topical regimen was very low. Twice-daily application of DDEA 2.32% gel to 2 knees for 7 days roughly doubled systemic exposure vs. application to 1 knee. Oral dosing with diclofenac sodium tablets (50 mg, three times daily) increased systemic exposure on Day 7 vs. topical dosing by 1–2 orders of magnitude. Local and systemic tolerability of topical DDEA gel were excellent.
Massey T, Derry S, Moore R, McQuay H. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev 2010; Issue 6. Art. No.: CD007402. DOI: 10.1002/14651858.CD007402.pub2.
Altman R, Barthel H. Topical therapies for osteoarthritis. Drugs 2011; 71(10):1259-1279.
Predel HG, Hamelsky S, Gold M, Giannetti B. Efficacy and safety of diclofenac diethylamine 2.32% gel in acute ankle sprain. Med Sci Sports Exercise 2012; 44(9):1629-1636.
Disclosure of Interest M. Armogida Shareholder of: shares, Employee of: Novartis OTC, M. Gold Employee of: Novartis OTC, G. Golor: None declared
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