Modeling of drug- and system-related changes in body temperature: application to drug-induced hypothermia, long-lasting tolerance development and diurnal variation in body temperature
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.