A pharmacokinetic/pharmacodynamic approach vs. a dose titration for the determination of a dosage regimen: the case of nimesulide, a Cox-2 selective nonsteroidal anti-inflammatory drug in the dog

The present experiment was designed to determine a dosage regimen (dose, in terval of administration) in the dog for nimesulide, a nonsteroidal anti-in flammatory drug with in vitro selectivity for the inhibition of cyclooxygen ase 2 (Cox-2), using a pharmacokinetic/pharmacodynamic (PK/PD) approach. Th e PK/PD results were compared with those obtained using a classical dose ti tration study. In the PK/PD experiment, 11 dogs were subjected to Freund's adjuvant arthritis characterized by permanent hyperthermia, Nimesulide (5 m g/kg, oral route) was tested during the secondary phase of the inflammatory response. In the dose titration study, nimesulide (0, 3, 6 and 9 mg/kg, or al route) was tested in eight other dogs using a reversible urate crystal a rthritis in a 4-period crossover design. Different PD endpoints (including lameness assessed by force plate and hyperthermia) were regularly measured during the PK/PD experiment, and plasma samples were obtained to determine the plasma nimesulide concentration. The data were modeled using an indirec t effect model. The IC50 of nimesulide for lameness was 6.26 +/- 3.01 mug/m L, which was significantly higher than the EC50 value obtained for antipyre tic effect (2.72 +/- 1.29 mug/mL). The ED50 estimated from the classical do se titration study were 1.34 mg/kg (lameness) and 3.0 mg/kg (skin temperatu re), The PK/PD parameters were used to simulate different dosage regimens ( dose, interval of administration). The antipyretic and anti-inflammatory ef fects were calculated from the model for the recommended dosage regimen (5 mg/kg/24 h). It was apparent from this approach, that this dosage regimen e nabled 76% of the theoretical maximal drug efficacy to be obtained for pyre sis and 43% for lameness. It was concluded from the comparison of in vivo a nd in vitro IC50, that nimesulide is a potent NSAID for which some Cox-1 in hibition is required to obtain clinically relevant efficacy.