PRECLINICAL AND CLINICAL DEVELOPMENT OF DEXKETOPROFEN

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSALD) ketopro fen. Racemic ketoprofen is used as an analgesic and an anti-inflammato ry agent, and is one of the most potent in vitro inhibitors of prostag landin synthesis. This effect is due to the S(+)-enantiomer (dexketopr ofen), while the R(-)-enantiomer is devoid of such activity. The pharm acokinetic profile of ketoprofen and its enantiomers was assessed in s everal animal species and in human volunteers. In humans, the relative bioavailability of oral dexketoprofen trometamol (12.5 and 15mg, resp ectively) is similar to that of oral racemic ketoprofen (25 and 50mg, respectively), as measured in all cases by the area under the concentr ation-time curve values for S(+)ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (t(max)) of between 0.25 and 0.75 hours. whereas the t(m ax) for the S-enantiomer after the racemic drug, administered as table ts or capsules prepared with the free acid, is between 0.5 and 3 hours . Peak plasma concentrations of 1.4 and 3.1 mg/L are reached after adm inistration of dexketoprofen trometamol 12.5 and 25mg, respectively. F rom 70 to 80% of the administered dose is recovered in the urine durin g the first 12 hours, mainly as the acyl-glucuronoconjugated parent dr ug. No R(-)-ketoprofen is found in the urine after administration of d exketoprofen [S(+)-ketoprofen]. confirming the absence of bioinversion of the S(+)-enantiomer in humans. In animal studies, the anti-inflamm atory potency of dexketoprofen was always equivalent to that demonstra ted by twice the dose of ketoprofen. Similarly, animal studies showed a high analgesic potency for dexketoprofen trometamol. The R(-)-enanti omer demonstrated a much lower potency, its analgesic action bring app arent only in conditions where the metabolic bioinversion to the S(+)- enantiomer was significant. The gastric ulcerogenic effects of dexketo profen at various oral doses (1.5 to 6 mg/kg) in the rat do not differ from those of the corresponding double doses (3 to 12, mg/kg) of race mic ketoprofen. Repeated (5-day) oral administration of dexketoprofen as the trometamol salt causes less gastric ulceration than was observe d after the acid form of both dexketoprofen and the racemate. In addit ion, single dose dexketoprofen as the free acid at 10 or 20 mg/kg does not show a significant intestinal ulcerogenic effect in rats, while r acemic ketoprofen 20 or 40 mg/kg is clearly ulcerogenic to the small i ntestine. The analgesic efficacy of oral dexketoprofen trometamol 10 a nd 20mg is superior to that of placebo and similar to that of ibuprofe n 400mg in patients with moderate to severe pain after third molar ext raction. The time to onset of pain relief appeared to be shorter in pa tients treated with dexketoprofen trometamol than in those treated wit h ibuprofen 400mg. Dexketoprofen trometamol was well tolerated, with a reported incidence of adverse events similar to that of placebo.