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Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2010 Jan; Vol. 159 (1), pp. 176-87. Date of Electronic Publication: 2009 Dec 02. - Publication Year :
- 2010
-
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.<br />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.<br />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=LT(0)/(1 +MED). LT(0) 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 microg*mL(-1).<br />Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.
- Subjects :
- Administration, Oral
Analgesics administration & dosage
Analgesics pharmacokinetics
Animals
Biological Availability
Carrageenan
Cyclooxygenase 2 Inhibitors administration & dosage
Cyclooxygenase 2 Inhibitors pharmacokinetics
Diclofenac administration & dosage
Diclofenac pharmacokinetics
Diclofenac pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Inflammation Mediators metabolism
Models, Biological
Nonlinear Dynamics
Rats
Rats, Wistar
Time Factors
Analgesics pharmacology
Cyclooxygenase 2 Inhibitors pharmacology
Diclofenac analogs & derivatives
Hyperalgesia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 159
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 19958362
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00508.x