Yu Fu1, M.M. Said1, P.H. van der Graaf1,2, J.G.C. van Hasselt1, N. Snelder3
1 System Biomedicine and Pharmacology, LACDR, Leiden University, the Netherlands 2 Certara QSP, Canterbury, UK 3 LAP&P Consultants BV, Leiden, the Netherlands
Objectives:
The cardiovascular hemodynamic system is complex and highly regulated by several physiological feedback mechanisms. Drugs may have distinct interactions with specific components of this system, either as adverse response or desired therapeutic effects. Previously a minimal quantitative systems pharmacology (QSP) model was built to quantify the cardiovascular drug effects for eight compounds in rat by Snelder et al. (“Snelder model”) characterizing drug effects on interrelationships between heart rate (HR), stroke volume (SV), total peripheral resistance (TPR), cardiac output (CO) and mean arterial pressure (MAP) [1,2]. However, CO is challenging to measure. Recently contractility-based readouts (e.g. dP/dtmax) have been proposed as alternative. The goal of the current analysis was to develop a mechanism-based hemodynamic model, which integrates and compares the use of both CO and contractility, and includes drug effects of atenolol, a selective β1 blocker in dog as proof-of-concept.
Methods:
HR, TPR, MAP, and contractility (dP/dtmax) data was obtained from three conscious Beagle dog telemetry studies for atenolol. Twelve animals were given three increasing oral doses of 0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg or 30mg/kg, or placebo. The model was defined according to a system of ordinary differential equations and a nonlinear mixed effect modeling framework. We first implemented the Snelder model, and subsequently included additional model components for hemodynamic biomarkers of dPdtmax, end-diastolic volume (EDV) and end-systolic volume (ESV) [1,2]. Pharmacokinetic parameters for atenolol in dog were fixed to literature values [3]. Circadian rhythms were investigated on HR, TPR and dP/dtmax. Inter-occasion variability of circadian rhythms was included due to differences in study designs and lack of information about the real clock time for observations and administrations. An Emax function was used to describe the negative effects on HR and contractility, in line with its mechanism of action.
Results:
The developed hemodynamic systems model captures the dynamics of biomarkers HR, TPR, dP/dtmax and MAP after administration of atenolol. The parameter estimates (%CV) for the baselines of hemodynamic biomarkers were BSLHR = 74.9 /min (2.3%), BSLMAP = 104 mmHg (3.39%), BSLCO = 2320 ml/min (32%), BSLCONTRM = 1350 mmHg/s (4.4%) for HR, MAP, CO and dP/dtmax, respectively. A negative effect on HR and contractility was supported by the model with potency estimates of EC50_HR = 58.5 ng/ml (46.4%) and EC50_contr = 869 ng/ml (130%). Cosine functions on turnover parameters of HR and dP/dtmax described the circadian rhythms observed in HR, dP/dtmax and MAP while circadian rhythms of TPR could not be identified.
Conclusions:
The developed model can be used to describe dynamic changes of contractility and other hemodynamic biomarkers (HR, TPR and MAP) for atenolol in dog, along with quantifying the drug effect on heart rate and contractility to assess the hemodynamic safety.
References:
[1] N. Snelder et al., “Drug Effects on the CVS in Conscious Rats: Separating Cardiac Output into Heart Rate and Stroke Volume Using PKPD Modelling,” British Journal of Pharmacology 171, no. 22 (2014)
[2] N. Snelder et al., “PKPD Modelling of the Interrelationship between Mean Arterial BP, Cardiac Output and Total Peripheral Resistance in Conscious Rats,” British Journal of Pharmacology 169, no. 7 (2013)
[3] James McAinsh and Brian F. Holmes, “Pharmacokinetic Studies with Atenolol in the Dog,” Biopharmaceutics & Drug Disposition 4, no. 3 (1983)
Reference: PAGE () Abstr 9369 [www.page-meeting.org/?abstract=9369]
Poster: Drug/Disease Modelling - Other Topics