Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase‐2, in rats

Abstract

Background and purpose:This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg -1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg -1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT = LT0/(1 + MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 mg·mL -1. Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.

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

“…Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) that is widely prescribed and used for relieving the pain and edema associated with inflammatory conditions, such as osteoarthritis and rheumatoid arthritis [1][2][3] . It is commonly known that diclofenac acts by potent cyclo-oxygenase (COX) inhibition, which decreases the formation of proinflammatory mediators, such as prostaglandins (PGs) [4] .…”

“…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.…”

Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

“…For example, a nonlinear function model was initially assayed to describe the time course of the second pain phase, in a manner analogous to the modeling of the pain response induced by injection of carrageenan in rats (9). This model was discarded as a poor fit was obtained.…”

“…Model performance was evaluated through visual and numerical predictive checks (VPC and NPC, respectively) (9). Five hundred studies of the same design characteristics as the original studies were simulated.…”

“…We have previously reported a PK/PD model which adequately describes the time course of the antinociceptive response of systemic lumiracoxib as a function of its inhibitory effect on COX-2 (9). However, it is well known that the overall antinociceptive response of NSAIDs (10)(11)(12), and particularly of lumiracoxib (13), depends on the actions at the site of inflammation as well as at the central nervous system (CNS).…”