Modeling the time-course of the antipyretic effects and prostaglandin inhibition in relation the analgesic effects of naproxen: a compound selection strategy
Sandra Visser(1), Elke Krekels(1), Kristina Ängeby Möller(2), Marie Angesjö(1), Ingemo Sjögren(1) and Odd-Geir Berge(2)
(1)DMPK and (2)Disease Biology, Local Discovery, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden
Objectives: This study aimed to characterize the pharmacokinetic-pharmacodynamic (PKPD) relationship between plasma concentrations, inhibition of TXB2 and PGE2 synthesis, and the antipyretic and analgesic effects of naproxen in rats in order to investigate whether analgesic measurements could be replaced by endpoints that are more sensitive for compound selection.
Methods: Analgesic effects: naproxen (0, 7.5 and 30 µmol/kg p.o.) was given 1h after an intra-articular injection of carrageenan. Weight bearing was assessed at 5 time points per rat using the PawPrint method and plasma concentrations were measured at 25h.
Antipyretic effects: fever was induced by a 2 g/kg s.c. injection of brewer's yeast 4h before naproxen (0, 7.5, 30 and 90 µmol/kg p.o.). Body temperature was measured continuously using telemetry up to 25h after dosing and plasma concentrations were measured at 25h.
Prostaglandin synthesis: TXB2 and PGE2 synthesis over time was measured ex vivo in separate animals using ELISA. Satellite animals were used to obtain the complete PK profile. The naproxen concentrations were analyzed using LC-ESI-MS/MS. Nonmem V was used for all PKPD modelling procedures.
Results: A two-compartment PK model described the concentrations of naproxen best. Fever was identified as a covariate on CL. Individual parameter estimates were used to predict the pharmacokinetic profiles to the analgesic and antipyretic effects.
A sigmoidal relationship between the naproxen concentrations and the inhibition of TXB2 and PGE2 synthesis was observed. Population estimates for potency were 5±1 and 13±4 µM, respectively. Inter-individual variation was around 35% whereas the residual variation was 15%.
A linear model was used to describe the relationship between weight bearing on the affected limb and the concentrations. A tolerance pool model was used to describe the concentration dependent reduction of fever and the observed rebound.
Naproxen was equipotent with respect to the antipyretic and analgesic effects. However, the variability in measurements was much larger and dose separation less clear for the analgesic effects.
Conclusions: The time-courses of the naproxen concentration, inhibition of TXB2 and PGE2 synthesis, antipyretic and analgesic effects in rats were quantified and correlated. Endpoints such as antipyretic effects or the inhibition of TXB2/PGE2 could serve as alternatives to analgesic measurements for identifying differences between compounds in lead optimization.