Safety pharmacology screening using a standardized population pharmacokinetic pharmacodynamic modelling approach
N. Snelder (2), T. van Steeg (2), B. Ploeger (2), N. Attkins (1), P. van der Graaf (1)
(1) Pfizer Global Research & Development, Sandwich, UK; (2) LAP&P Consultants, Leiden, The Netherlands
Objectives: Translational PKPD modelling has been recognized as an efficient tool for bringing forward early insights in drug efficacy and safety into the clinical development stage [1]. In respect to safety, detailed understanding of the safety pharmacology of NCE's early in development is essential to better predict potential safety issues in the clinic. At Pfizer, the safety pharmacology of lead compounds is routinely investigated in rats using a standardized study design, resulting in a high volume (up to several studies per week) of studies that require rapid PKPD analysis. In order to make efficient use of this information in making timely go-no go decisions, we propose a standardized PKPD modelling approach for estimating the PKPD relationship of possible effects on cardiovascular side effects, such as changes in heart rate and blood pressure. This approach also allows less experienced modellers to report the PKPD relationship, including a simulation of the concentration resulting in a pre-defined effect level, within 2 days after receiving the data.
Methods: Using data from six studies, a standardized population PKPD modelling approach was developed, providing guidance on how to estimate the PKPD relationship for a specific compound in a practical and efficient manner. The data were obtained from experiments in which heart rate and blood were measured in telemetry implemented rats. This approach was validated using data from three other compounds.
Results: The standardized PKPD modelling approach provided detailed guidance on the modelling process, i.e. which models should be evaluated and how to interpret the modelling results, to identify the best PKPD relationship considering available data and timelines. Following this approach, three modellers with different modelling experience reported the same PK-PD relationship for all compounds within two days after receiving the data.
Conclusion: The developed standardized PKPD modelling approach for safety pharmacology screening allows quick and easy identification of the concentration- (side) effect relationships of discovery compounds in a routine based setting. We are currently in the process of implementing this approach into a desktop tool which will perform most of the analysis in a semi-automated manner. Currently, this approach has been validated to describe data from one type of rat study. However, it is foreseen that this standardized approach can be applied to other study designs also. Such a standardised approach towards PKPD analysis may also have applications outside safety testing.
References:
[1] Danhof, M., de Lange, E.C., Della Pasqua, O.E., Ploeger, B.A. and Voskuyl, R.A.: Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research. Trends Pharmacol Sci, 29: 186-91. Epub 2008 Mar 18. (2008)
