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.

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression

“…Yet aspirin, a COX-1 preferential inhibitor, is one of the most effective antipyretic NSAIDs, and inhibits fever at doses ranging from 5-15 mg/kg (29), far below the 60-80 mg/kg used to treat inflammatory disease (30,31). Furthermore, nimesulide, a COX-2 preferential inhibitor, was found to be antipyretic in dogs only at plasma concentrations that would also inhibit COX-1 (32). Thus, a role for COX-1 in fever may exist.…”

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

“…Pharmacokinetic-pharmacodynamic (PK-PD) modeling represents a powerful tool to quantitatively describe the pharmacokinetic, pharmacodynamic and systemrelated processes [5] . Several attempts have been made to illustrate the relationship between the plasma concentrationtime profiles of NSAIDs and the pharmacological activity of these drugs using two types of traditional pharmacological endpoints: (i) those exploring the inflammatory response and having a mechanistic interest, such as central and local hyperthermia (body and skin temperature), hyperalgesia (pain score) and edema (paw volume) and (ii) the hybrid endpoints that have direct clinical relevance and reflect both the pain and functional impairments [2,[6][7][8][9][10][11] . However, these studies have disregarded the direct relationship between the drug concentration and the pharmacological response to COX inhibition.…”

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling of antipyretic effect of meloxicam: A preferential cyclooxygenase inhibitor in rat

“…Also, PK/PD modeling can be used to find out sensitive, efficacious and toxic dose. Only limited insights on in vivo NSAIDs pharmacokinetics and pharmacodynamics (Toutain et al, 1994(Toutain et al, , 2001Lees, 2003) are available, a few preclinical studies have been conducted to model blood or plasma concentration-time profiles. Especially for antipyretic activity, ibuprofen has been modeled in children to biophase concentration (Kelly et al, 1992;Brown et al, 1988) and to plasma concentration (Garg and Jusko, 1994) with indirect response models.…”