PHARMACOKINETIC COMPARISON OF ORAL AND LOCAL-ACTION TRANSCUTANEOUS FLURBIPROFEN IN HEALTHY-VOLUNTEERS

Flurbiprofen is a propionic acid-derived nonsteroidal anti-inflammatory drug (NSAID) used widely in the treatment of rheumatism and non-arthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two-part, open study involving healthy adult volunteers. In the first (cross-over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen-containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen-containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high-performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (C-max) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean+/-SD: 43 +/- 16 ng/ml versus 5999 +/- 1300 ng/ml, respectively). After repeated application of the topical patch, C-max increased only slightly to 103 +/- 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3.5 +/- 1.7%, calculated from plasma area under the curve data and 4.4 +/- 2.8% from urinary excretion data. The temporal profile of the appearance of flurbiprofen in the circulation also differed, with maximum concentrations occurring (T-max) 2 +/- 1 h after the oral dose but not until 20 +/- 6 h of applying the first patch, decreasing to 4 +/- 3 h after repeated applications. Steady-state plasma concentrations were reached within 5 days of repeated patch applications; these exhibited intersubject variability ranging from 32 to 285 ng/ml Percutaneous absorption of fluriprofen from the patch into the systemic circulation was thus relatively slow and systemic concentrations of the drug achieved by this route were much lower than those obtained after oral intake of comparable doses. The systemic concentrations achieved via the topical route are likely to be insufficient to account for the demonstrable efficacy of the formulation in clinical trials, which is considered to depend on local enhanced topical delivery of flurbiprofen. Moreover, it might reasonably be supposed that the use of the flurbiprofen-containing patch as a localized treatment for musculoskeletal soft-tissue lesions will elicit a lower incidence of systemic adverse effects than occurs with the orally administered NSAID.