title: 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.
abstract: The present experiment was designed to determine a dosage regimen (dose, interval of administration) in the dog for nimesulide, a nonsteroidal anti-inflammatory drug with in vitro selectivity for the inhibition of cyclo-oxygenase 2 (Cox-2), using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The PK/PD results were compared with those obtained using a classical dose titration study. In the PK/PD experiment, 11 dogs were subjected to Freund's adjuvant arthritis characterized by permanent hyperthermia. Nimesulide (5 mg/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, oral route) was tested in eight other dogs using a reversible urate crystal arthritis 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 indirect effect model. The IC50 of nimesulide for lameness was 6.26 +/- 3.01 microg/mL, which was significantly higher than the EC50 value obtained for antipyretic effect (2.72 +/- 1.29 microg/mL). The ED50 estimated from the classical dose titration study were 1.34 mg/kg (lameness) and 3.0 mg/kg (skin temperature). The PK/PD parameters were used to simulate different dosage regimens (dose, interval of administration). The antipyretic and anti-inflammatory effects 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 enabled 76% of the theoretical maximal drug efficacy to be obtained for pyresis and 43% for lameness. It was concluded from the comparison of in vivo and in vitro IC50, that nimesulide is a potent NSAID for which some Cox-1 inhibition is required to obtain clinically relevant efficacy.
authors.affiliation: Unité Associée INRA de Physiopathologie et Toxicologie Expérimentales, Ecole Nationale Vétérinaire, Toulouse, France. pl.toutain@envt.fr
authors.forename: P L
authors.initials: PL
authors.lastname: Toutain
authors.forename: C C
authors.initials: CC
authors.lastname: Cester
authors.forename: T
authors.initials: T
authors.lastname: Haak
authors.forename: V
authors.initials: V
authors.lastname: Laroute
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001168:Arthritis / Q000188:drug therapy / Q000662:veterinary*; D018592:Cross-Over Studies; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000188:drug therapy / Q000662:veterinary; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007794:Lameness, Animal / Q000188:drug therapy; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D005620:Freund's Adjuvant; C012655:nimesulide