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Preclinical and Clinical Development of Dexketoprofen

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Summary

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the S(+)-enantiomer (dexketoprofen), while the R(−)-enantiomer is devoid of such activity.

The pharmacokinetic profile of ketoprofen and its enantiomers was assessed in several animal species and in human volunteers. In humans, the relative bioavailability of oral dexketoprofen trometamol (12.5 and 25mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50mg, respectively), as measured in all cases by the area under the concentration-time curve values for S(+)-ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) of between 0.25 and 0.75 hours, whereas the tmax for the S-enantiomer after the racemic drug, administered as tablets 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 administration of dexketoprofen trometamol 12.5 and 25mg, respectively.

From 70 to 80% of the administered dose is recovered in the urine during the first 12 hours, mainly as the acyl-glucuronoconjugated parent drug. No R(−)-ketoprofen is found in the urine after administration of dexketoprofen [S(+)-ketoprofen], confirming the absence of bioinversion of the S(+)-enantiomer in humans.

In animal studies, the anti-inflammatory potency of dexketoprofen was always equivalent to that demonstrated by twice the dose of ketoprofen. Similarly, animal studies showed a high analgesic potency for dexketoprofen trometamol. The R(−)-enantiomer demonstrated a much lower potency, its analgesic action being apparent only in conditions where the metabolic bioinversion to the S(+)-enantiomer was significant.

The gastric ulcerogenic effects of dexketoprofen 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 racemic ketoprofen. Repeated (5-day) oral administration of dexketoprofen as the trometamol salt causes less gastric ulceration than was observed after the acid form of both dexketoprofen and the racemate. In addition, single dose dexketoprofen as the free acid at 10 or 20 mg/kg does not show a significant intestinal ulcerogenic effect in rats, while racemic ketoprofen 20 or 40 mg/kg is clearly ulcerogenic to the small intestine.

The analgesic efficacy of oral dexketoprofen trometamol 10 and 20mg is superior to that of placebo and similar to that of ibuprofen 400mg in patients with moderate to severe pain after third molar extraction. The time to onset of pain relief appeared to be shorter in patients treated with dexketoprofen trometamol than in those treated with ibuprofen 400mg. Dexketoprofen trometamol was well tolerated, with a reported incidence of adverse events similar to that of placebo.

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  1. Research and Development Department, Laboratorios Menarini SA, Alfonso XII 587, 08912, Barcelona, Spain

    David Mauleón (R&D Director), Remei Artigas & M. Luisa García

  2. Menarini Ricerche Sud, Florence, Italy

    Germano Carganico

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  1. David Mauleón
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Mauleón, D., Artigas, R., García, M.L. et al. Preclinical and Clinical Development of Dexketoprofen. Drugs 52 (Suppl 5), 24–46 (1996). https://doi.org/10.2165/00003495-199600525-00005

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