A Pharmacodynamic Turnover Model Capturing Asymmetric Circadian Baselines of Body Temperature, Heart Rate and Blood Pressure in Rats: Challenges in Terms of Tolerance and Animal-handling Effects |
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Authors: | Björn Sällström Sandra A G Visser Tomas Forsberg Lambertus A Peletier Ann-Christine Ericson Johan Gabrielsson |
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Institution: | 1. PKPD section, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D S?dert?lje, B231, SE-151 85, S?dert?lje, Sweden 2. Department of General Pharmacology, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D S?dert?lje, SE-151 85, S?dert?lje, Sweden 3. Mathematical Institute, Leiden University, Niels Bohrweg 1, P.O. Box 9512, 2300, RA, Leiden, The Netherlands 4. Centrum voor Wiskunde en Informatica, P.O. Box 94079, 1090?GB, Amsterdam, The Netherlands 5. DMPK & Bioanalytical Chemistry, AstraZeneca R&D M?lndal, AP305, SE-431 83, M?lndal, Sweden
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Abstract: | This study presents development and behaviour of a feedback turnover model that mimics asymmetric circadian oscillations of
body temperature, blood pressure and heart rate in rats.The study also includes an application to drug-induced hypothermia,
tolerance and handling effects. Data were collected inn normotensive Sprague-Dawley rats, housed at 25 °C with a 12:12 hr
light dark cycle (light on at 06:00 am) and with free access of food and water. The model consisted of two intertwined parallel
compartments which captured a free-running rhythm with a period close to but not exactly 24 hrs. The free-running rhythm was
synchronised to exactly 24 hrs by the environmental timekeeper (12:12 hr light on/off cycle) in experimental settings. The
baseline model was fitted to a standardised 24-hr period derived from mean data of six animals over a period of nine consecutive
days. The first-order rate constants related to the turnover of the baseline temperature, α and β, were 0.026 min−1 (±5%) and 0.0037 min−1 (±3%). The α and β parameters are approximately 2/transition time between day and night and 2/night time, respectively. The
day:night timekeeper g(t), reference point Tref and amplitude were 0.053(±2%),37.3(±0.02%) and 3.3% (±2%), respectively. Simulations with the baseline model revealed stable oscillations
(free-running rhythm) in the absence of the timekeeper. This temperature–time profile was then symmetric and had a smaller amplitude, with a slightly shorter period and less pronounced temperature shift
as compared to the profile in the presence of an external Timekeeper. Fitting the model to 96 hr mean profiles of blood pressure
and heart rate from 10 control animals demonstrated the usefulness of the model.Simulations of the integrated temperature
model succeeded in mimicking other modes of administration such as oral dosing |
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Keywords: | pharmacodynamics turnover model mathematical model set-point free-running rhythm circadian rhythm oscillating model chronobiology Zeitgeber |
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