Comparison of the anti‐inflammatory actions of flunixin and ketoprofen in horses applying PK/PD modelling

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Abstract
A comparative study in horses of the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 extensively used nonsteroidal anti-inflammatory drugs (NSAIDs), flunixin (FXN) and ketoprofen (KTP), was carried out applying PK/PD modelling. To evaluate the anti-inflammatory properties of these drugs a model of acute inflammation, comprising surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. FXN elimination half-life (T1/2β) in plasma was 3.37 ± 1.09 h. However, in exudate a much longer T1/2β was obtained (15.99 ± 3.80 h). Apparent volume of distribution (Vdarea) for FXN was 0.317 ± 0.126 1/kg and body clearance (CIB) was 0.058 ± 0.004 1/kg/h. KTP displayed enantioselective pharmacokinetics, the S(+) enantiomer being predominant in plasma, exudate and transudate. T1/2β values for R(-) and S(+)KTP were, respectively, 1.09 ± 0.19 h and 1.51 ± 0.45 h (plasma) and 19.73 ± 2.72 h and 22.64 ± 4.34 h (exudate), respectively. R(-)KTP was cleared more rapidly than the S(+) enantiomer. C1B values were 0.277 ± 0.035 1/kg/h and 0.202 ± 0.022 1/kg/h, respectively. FXN and KTP pharmacodynamics was evaluated by determining their inhibitory effects on serum thromboxane (Tx)B2, exudate prostaglandin (PG)E2, leukotriene (LT)B4 and β-glucuronidase (β-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB2 synthesis for up to 24 h, with no significant differences between the drugs. FXN was a more potent inhibitor of exudate PGE2, the EC50 for FXN being lower (P4 concentration. Differences between the 2 drugs were observed for the inhibition of β-glu, the Emax for KTP being higher (P1/2Ke0) also differed, being much longer (Pin vitro methods that it provides data in the whole animal. By quantifying action-concentration interrelationships through PK-PD modelling, it is possible to shed light on molecular mechanisms of drug action, and establish probable differences in mechanisms of action between structurally similar drugs. In future it should be possible to use PK/PD modelling to provide a rational basis for selecting dosage schedules for clinical use.