PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats

Abstract

BACKGROUND AND PURPOSEThe homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP. Hence, we aimed to develop a mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action (MoA) on the interrelationship between BP, CO and TPR. EXPERIMENTAL APPROACHThe cardiovascular effects of six drugs with diverse MoA, (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP. Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism-based PKPD modelling approach. KEY RESULTSBy simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP, CO and TPR were quantified. System-specific parameters could be distinguished from drug-specific parameters indicating that the model developed is drug-independent. CONCLUSIONS AND IMPLICATIONSA system-specific model characterizing the interrelationship between BP, CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data. AbbreviationsAmp, amplitude; BSL_CO, baseline value of cardiac output; BSL_MAP, baseline value of MAP; BSL_TPR, baseline value of total peripheral resistance; C, drug concentration in plasma; CO, cardiac output; Emax, maximum effect; FB1, negative feedback of mean arterial pressure on cardiac output; FB2, negative feedback of mean arterial pressure on total peripheral resistance; HCTZ, hydrochlorothiazide; HOR, horizontal displacement; IIV, inter-individual variability; Kin_CO, zero-order production rate constant of cardiac output; Kin_TPR, zero-order production rate constant of total peripheral resistance; kout_CO, first-order dissipation rate constant of cardiac output; kout_TPR, first-order dissipation rate constant of total peripheral resistance; MAP, mean arterial pressure; MC, methylcellulose; MoA, mechanisms of action; MVOF, minimum value of the objective function;

Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling

“…Previously, we developed a mechanism-based linked turnover model to describe the interrelationship between MAP, CO and TPR (Snelder et al, 2013a). This model consisted of two turnover equations, one for CO and one for TPR, which were linked by negative feedback through MAP representing homeostatic feedback mechanisms such as the baroreflex system (Cleophas, 1998) …”

“…For continuous recording of BP, HR and CO, rats were surgically instrumented with both an ascending aortic flow probe and a femoral arterial catheter/radiotransmitter as described by Snelder et al (2013a).…”

“…The number of dose strengths investigated varied for each drug in order to find an appropriate dose showing a clear effect, and, therefore, the duration of the study also varied for each drug. The MAP and CO measurements following the administration of amlodipine, prazosin and HCTZ (first occasion) in SHR were also used for the development of the previous CVS model (Snelder et al, 2013a). As these data are also informative for the proposed extended CVS model, they are included in this investigation as well.…”

“…Moreover, it has the advantage that a single dose/concentration-effect relationship can be established. Previously, it was demonstrated that drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) can be quantified using a systems pharmacology model (Snelder et al, 2013a). As CO equals the product of HR and stroke volume (SV), it is anticipated that this model can be extended to a more detailed level by parsing CO into HR and SV with the advantage that drug effects on MAP, CO, HR, SV and TPR can be characterized simultaneously.…”

“…As CO equals the product of HR and stroke volume (SV), it is anticipated that this model can be extended to a more detailed level by parsing CO into HR and SV with the advantage that drug effects on MAP, CO, HR, SV and TPR can be characterized simultaneously. It has been demonstrated that the previously developed CVS model (basic CVS model) can be applied to elucidate the MoA of novel compounds (Snelder et al, 2013a). This requires continuous recording of CO.…”