Annika Brings, Eric Martel, Wolfgang Rist, Robert Augustin, Stefan Scheuerer and Brian Guth
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
Objectives: To develop a PK/PD model of adverse, drug-mediated increase in heart rate in the anaesthetized mouse in order to determine a dose with acceptable heart rate alterations (defined as < 10% increase relative to baseline).
Methods: PK data were obtained in C57BL/6NCrl or Rj:SWISS mice following an i.v. bolus injection of drug A, B or C. For assessment of cardiovascular effects, arterial blood pressure, heart rate (HR) and body temperature were continuously measured in anaesthetized, male Swiss mice for up to 95 min. Baseline values were collected for 5 min prior to i.v. injection of drug A, B, or C, or vehicle. Plasma samples for exposure measurements were obtained for 1-3 time points in this study. Plasma concentrations were fitted to a pharmacokinetic model using non-linear modelling with the naïve pooled approach implemented in Phoenix WinNonlin 6.3. Heart rate data were fitted either to a turnover model with saturable stimulation of build-up, or to a receptor binding model [1].
Results: PK data could be described with a one-compartment (drug A) or two-compartment model (drugs B+C). Due to the low drug clearance (~0.01 L/hr/kg) a step-wise increase in plasma concentrations could be achieved using sequential, escalating i.v. bolus doses (3, 10, 30 and 100 µg/kg at 0, 15, 30 and 45 min) to study the concentration dependence of cardiovascular effects. This showed a dose-dependent increase in HR and a time delay between plasma concentration and effect, suggesting that the emergence of HR effects takes longer than 15 min. The time delay could be described by a turnover model, which was used to predict the time and magnitude of the maximum effect and to plan a further study with HR monitoring for up to 90 min following a single i.v. injection of compound C at 6 different doses. In this study the maximum HR effect occurred at ≥ 60 min after drug administration. HR effects were emerging slower than predicted by the turnover model and were described more adequately by a receptor binding model. Turnover and distributional delay models yielded poorer fits as assessed by predictive check. The receptor binding model predicted an acceptable dose of 40 µg/kg.
Conclusion: The observed time delay between plasma concentration and HR increase was best described by a receptor binding model, suggesting that receptor binding kinetics may be responsible for the slow emergence of HR effects. Further studies would be required to investigate the mechanism of HR increase.
References:
[1] Shimada S, Nakajima Y, Yamamoto K, Sawada Y, Iga T. Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients. Biol Pharm Bull (1996) 19(3): 430-437.
Reference: PAGE 24 () Abstr 3324 [www.page-meeting.org/?abstract=3324]
Poster: Drug/Disease modeling - Safety