{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:57:28Z","timestamp":1790744248369,"version":"4.1.0"},"reference-count":14,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Diclofenac is a widely used topical nonsteroidal anti\u2010inflammatory 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\u2010six adults aged \u226550 years were enrolled in a single\u2010center, open\u2010label, randomized, two\u2010arm, three\u2010way crossover study consisting of three 7\u2010day treatment periods separated by 14\u2010day 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\u2010h urine samples were collected on Days 1 and 7 using a validated LC\u2010MS\/MS assay. Systemic exposure (AUC\n                    <jats:sub>0\u201324<\/jats:sub>\n                    ) of DEA gel versus DS gel was comparable (GMR 90.7%; 90% CI: 82.7\u201399.5). Heat resulted in an excursion of the lower bound of the AUC\n                    <jats:sub>0<\/jats:sub>\n                    \u2010\n                    <jats:sub>24<\/jats:sub>\n                    90% confidence interval below the standard lower bioequivalence bound of 80% (GMR 92.5%; 90% CI: 77.3\u2013111.0), while exercise showed no meaningful effect (GMR 103%; 90% CI: 87.8\u2013120.0). As expected, given similar plasma exposure between treatments, urinary excretion was also similar (\u223c0.5% of the administered dose), supporting comparable systemic disposition.\n                  <\/jats:p>","DOI":"10.1002\/cpdd.70091","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:17:56Z","timestamp":1790741876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Bioavailability of Topical Diclofenac: Sodium 1% Versus Diethylamine 1.16% and the Effect of Heat or Exercise in a Randomized Cross\u2010Over Study"],"prefix":"10.1002","volume":"15","author":[{"given":"Karin","family":"Nicholson","sequence":"first","affiliation":[{"name":"Haleon  Warren NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Armogida","sequence":"additional","affiliation":[{"name":"Haleon CH SARL  Nyon Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris S.","family":"Gold","sequence":"additional","affiliation":[{"name":"IQVIA  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Desjardins","sequence":"additional","affiliation":[{"name":"Rutgers School of Dental Medicine  Newark NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2020.114147","article-title":"Non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs) and organ damage: a current perspective","volume":"180","author":"Bindu S","year":"2020","journal-title":"Biochem Pharmacol"},{"issue":"7","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1185\/03007995.2010.486301","article-title":"Diclofenac: an update on its mechanism of action and safety profile","volume":"26","author":"Gan TJ","year":"2010","journal-title":"Curr Med Res Opin"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.prostaglandins.2012.08.006","article-title":"Prostanoids and inflammatory pain","volume":"104","author":"Chen L","year":"2013","journal-title":"Prostaglandins Other Lipid Mediat"},{"issue":"9894","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S0140-6736(13)60900-9","article-title":"Vascular and upper gastrointestinal effects of non\u2010steroidal anti\u2010inflammatory drugs: meta\u2010analyses of individual participant data from randomised trials","volume":"382","author":"Coxib and traditional NSAID Trialists\u2019 (CNT) Collaboration","year":"2013","journal-title":"Lancet"},{"issue":"6","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.clinthera.2014.04.012","article-title":"Relationship between diclofenac dose and risk of gastrointestinal and cardiovascular events: meta\u2010regression based on two systematic literature reviews","volume":"36","author":"Odom DM","year":"2014","journal-title":"Clin Ther"},{"issue":"9","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/cpdd.1560","article-title":"Two phase I, randomized, open\u2010label, multiple\u2010dose, crossover studies investigating the systemic bioavailability of topical diclofenac diethylamine gels compared with oral diclofenac tablets","volume":"14","author":"Andersen G","year":"2025","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"5","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1097\/MJT.0b013e3182459abd","article-title":"Topical nonsteroidal anti\u2010inflammatory drugs: the importance of drug, delivery, and therapeutic outcome","volume":"22","author":"Barkin RL","year":"2015","journal-title":"Am J Ther"},{"issue":"12","key":"e_1_2_10_9_1","first-page":"2384","article-title":"Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee","volume":"32","author":"Niethard FU","year":"2005","journal-title":"J Rheumatol"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1186\/s12891-022-06077-z","article-title":"Randomized, double\u2010blind, noninferiority study of diclofenac diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily in patients with acute ankle sprain","volume":"23","author":"Yin F","year":"2022","journal-title":"BMC Musculoskelet Disord"},{"issue":"3","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.apmr.2021.06.015","article-title":"Local heat applications as a treatment of physical and functional parameters in acute and chronic musculoskeletal disorders or pain","volume":"103","author":"Clijsen R","year":"2022","journal-title":"Arch Phys Med Rehabil"},{"issue":"1","key":"e_1_2_10_12_1","first-page":"1","article-title":"Sample size determination for bioequivalence assessment by means of confidence intervals","volume":"29","author":"Diletti E","year":"1991","journal-title":"Int J Clin Pharmacol Ther Toxicol"},{"issue":"1","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1177\/0091270009336234","article-title":"Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers","volume":"50","author":"Kienzler JL","year":"2010","journal-title":"The Journal of Clinical Pharmacology"},{"issue":"5","key":"e_1_2_10_14_1","first-page":"399","article-title":"Physiologically\u2010based pharmacokinetic modeling to support bioequivalence and approval of generic products: a case for diclofenac sodium topical gel, 1%","volume":"10","author":"Tsakalozou E","year":"2021","journal-title":"CPT: Pharmacometrics Syst Pharmacol"},{"issue":"3","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1007\/s40122-025-00723-9","article-title":"Evaluating the real\u2010world use of topical diclofenac sodium gel 1% using US longitudinal electronic health records database: a study supporting OTC switch","volume":"14","author":"Sicignano NM","year":"2025","journal-title":"Pain Ther"}],"container-title":["Clinical Pharmacology in Drug 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