Sandra A.G. Visser (1), Björn Sällström (1), Tomas Forsberg (2), Svante B. Ross (3), Lambertus A. Peletier (4) and Johan Gabrielsson (1)
(1) PK/PD DMPK&BAC, (2) General Pharmacology, (3) Bioscience, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. (4) Mathematical Institute, Leiden University, Niels Bohrweg 1, P.O. Box 9512, 2300 RA, Leiden, The Netherlands.
Objectives: Clomethiazole (CMZ), an agonist for the GABA(A) receptor, has been shown to induce rapid and long lasting tolerance to its hypothermic effects in rats. However, quantification of the drug- and system-related changes in body temperature is complicated by a diurnal variation in body temperature and an influence of handling. Therefore, the objective of the present investigation was to develop a model for the characterization of diurnal variation in baseline, animal handling effects, CMZ-induced hypothermia and tolerance development.
Methods: CMZ-induced hypothermia and tolerance development was characterized using body temperature telemetry in male Sprague Dawley rats after subcutaneous (sc) bolus administration of 0, 15, 150, 300 and 600 µmol/kg and 24 h continuous administration of 0, 20 and 40 µmol/kg/h using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 µmol/kg with 3-30 days interval. Plasma exposure to CMZ was obtained in different groups of catheterized rats.
Results: Concentration-time profiles of CMZ displayed typical nonlinear kinetics with increasing dose and quantified with a two-compartment model with capacity-limited elimination. Simulated individual concentration-time profiles served as input to the pharmacodynamic model. The asymmetric diurnal variation in body temperature was successfully described with a negative feedback model, which was subject to external light-dark conditions. An exponential function characterized the animal handling effects. The baseline behavior was fed into a feedback model for temperature regulation allowing estimation of CMZ potency. The long lasting tolerance was described by inactivation of a moderator with an estimated turnover half-life of 30 days.
Conclusions: A pharmacokinetic-pharmacodynamic model featuring components for description of diurnal variation in baseline and influence of handling was able to quantify the CMZ-induced hypothermia and tolerance development in rats.
Reference: PAGE 13 () Abstr 512 [www.page-meeting.org/?abstract=512]
Poster: poster