• Garen Manvelian, Stephen Daniels, and Allan Gibofsky.
• Iroko Pharmaceuticals, Philadelphia, PA, USA.
• Postgrad Med. 2012 Jan 1; 124 (1): 117-23.

IntroductionThere is a clinical need for new nonsteroidal anti-inflammatory drugs (NSAIDs) and/or new formulations that, at minimum, retain the established efficacy of standard NSAIDs while minimizing their associated adverse events. This phase 1 clinical trial characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano-formulated, lower-dose oral diclofenac (nano-formulated diclofenac) compared with oral diclofenac in healthy subjects.MethodsA single-center, single-dose, randomized, open-label, 5-period, 5-treatment, 10-sequence crossover study was completed in 30 healthy subjects. Subjects received either nano-formulated diclofenac 18 mg or 35 mg or diclofenac 50 mg in fed and fasting states. The maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), terminal elimination half-life (T1/2), and area under the concentration time curve (AUC), along with safety and tolerability, were assessed.ResultsMean (± standard deviation) Tmax for nano-formulated diclofenac 18 (0.62 ± 0.35 h) and 35 mg (0.59 ± 0.20 h) demonstrated faster absorption than diclofenac 50 mg (0.80 ± 0.50 h). The T1/2 was similar between nano-formulated diclofenac 35 mg and diclofenac 50 mg (1.85 ± 0.45 h vs 1.92 ± 0.38 h, respectively). The Cmax for nano-formulated diclofenac 35 mg and diclofenac 50 mg was comparable in fasted subjects (1347 ± 764 ng/mL vs 1316 ± 577 ng/mL, respectively), but lower in fed subjects (524 ± 222 ng/mL vs 951 ± 391 ng/mL, respectively). As anticipated, there was a 19% reduction in drug exposure (AUC0(-∞)) when subjects received nano-formulated diclofenac 35 mg compared with diclofenac 50 mg under fasting conditions (1225 ± 322 h*ng/mL vs 1511 ± 389 h*ng/mL, respectively). Safety and tolerability were comparable between nano-formulated diclofenac and diclofenac.ConclusionThe novel nano-formulated, lower-dose diclofenac demonstrated lower systemic exposure, comparable Cmax, and faster absorption compared with diclofenac. In light of the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may permit use of lower NSAID doses that improve safety and tolerability while, at minimum, relieving pain similar to standard formulations.

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