Snelder, N, Ploeger, BA, Luttringer, O, Rigel, DF, Fu, F, Beil, M, Stanski, DR and Danhof, M (2014) Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling. British Journal of Pharmacology. pp. 5076-5092.

Abstract

Background and PurposePreviously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements.Experimental ApproachCardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach.Key ResultsThe extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects.Conclusions and ImplicationsA systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established

Item Type:	Article
Additional Information:	NIBR author: Rigel, DF institute: NIBR contributor address: Leiden Acad Ctr Drug Res, Gorlaeus Labs, Div Pharmacol, Leiden, Netherlands m.danhof@lacdr.leidenuniv.nl; Novartis, Modeling & Simulat Dept, Basel, Switzerland ; Novartis Pharmaceut, Novartis Inst BioMed Res, E Hanover, NJ USA ; Leiden Acad Ctr Drug Res, Gorlaeus Labs, Div Pharmacol, Leiden, Netherlands; Danhof, M; Leiden Univ, Leiden Acad Ctr Drug Res, Leiden, Netherlands
Date Deposited:	13 Oct 2015 13:11
Last Modified:	13 Oct 2015 13:11
URI:	https://oak.novartis.com/id/eprint/24927