Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling

Abstract

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 μg/mL and an IC(50) for R-ketoprofen of 1.6 μg/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.

Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs

“…The pharmacokinetic parameters of both enantiomers after IM administration were similar to those reported by Fosse [31] in piglets, despite the pigs in our study being older than those used in their study. T max and AUC S /AUC R ratio after oral administration were higher in our study than in the study reported by Neirinckx [14].…”

“…The absolute bioavailability of both ketoprofen enantiomers after IM administration is suggested to be almost complete [13,31]. After PO administration the bioavailability is reported to be approximately 85 % for both enantiomers [14].…”

“…Fosse [31] reported an IC 50 for S-ketoprofen of 26.7 μg/mL and an IC 50 for R-ketoprofen of 1.6 μg/mL from mechanical nociceptive threshold testing in the kaolin-induced inflammation model in neonatal pigs. There have been no other reports on either the total or the enantiospecific therapeutic target concentration of ketoprofen in plasma in pigs.…”

Randomised trial of the bioavailability and efficacy of orally administered flunixin, carprofen and ketoprofen in a pain model in sheep

“…Therapeutic levels have been reported for ketoprofen enantiomers in pigs, with concentrations of 26.7 μg/mL for S-ketoprofen and 1.6 μg/mL for R-ketoprofen. 31 Maximum concentrations were 7.42 mg/L for S-ketoprofen and 2.55 mg/L for R-ketoprofen when administered orally in pigs. 32 The concentration of ketoprofen in plasma was 4.5-8.4 μg/mL in our sheep at 2 h after administration and R-ketoprofen has been recorded as the most prominent enantiomer found in sheep.…”

A Review of Pain Assessment in Pigs

“…To determine the analgesic efficacy of ketoprofen in piglets, a handheld algometer was used to quantify mechanical thresholds pre- and posttreatment. The higher thresholds recorded in the ketoprofen-treated group compared to the placebo group suggested an anti-nociceptive effect between 12 and 24 h after drug administration, through the reduction of sensitivity of the peripheral nerve receptors (136). …”