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

Snelder, Nelleke; Ploeger, Bart; Luttringer, Olivier; Rigel, Dean F.; Fu, Feng; Beil, Michael E.; Stanski, Donald R.; Danhof, Meindert

doi:10.1111/bph.12824

Cited by 29 publications

(84 citation statements)

References 43 publications

(63 reference statements)

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“…Given the large numbers of genetically manipulated strains of mice that are available, the techniques described in this manuscript should also be useful for determining the hemodynamic mechanisms whereby targeted genetic alterations influence the 24 h pattern of blood pressure. In addition, as proposed by Snelder and colleagues (Snelder et al 2013(Snelder et al , 2014, we anticipate that these kinds of studies of the 24 h patterns of cardiac output and peripheral resistance will be useful for investigating the hemodynamic mechanisms that mediate the effects of different antihypertensive drugs on 24 h blood pressure profiles. Finally, such studies may help determine if the manner in which an antihypertensive drug affects 24 h profiles of cardiac output and peripheral resistance can influence cardiovascular outcomes independent of drug effects on the 24 h blood pressure profile.…”

Section: Perspectivementioning

confidence: 90%

The 24 h pattern of arterial pressure in mice is determined mainly by heart rate-driven variation in cardiac output

2014

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Few studies have systematically investigated whether daily patterns of arterial blood pressure over 24 h are mediated by changes in cardiac output, peripheral resistance, or both. Understanding the hemodynamic mechanisms that determine the 24 h patterns of blood pressure may lead to a better understanding of how such patterns become disturbed in hypertension and influence risk for cardiovascular events. In conscious, unrestrained C57BL/6J mice, we investigated whether the 24 h pattern of arterial blood pressure is determined by variation in cardiac output, systemic vascular resistance, or both and also whether variations in cardiac output are mediated by variations in heart rate and or stroke volume. As expected, arterial pressure and locomotor activity were significantly (P < 0.05) higher during the nighttime period compared with the daytime period when mice are typically sleeping (+12.5 ± 1.0 mmHg, [13%] and +7.7 ± 1.3 activity counts, [254%], respectively). The higher arterial pressure during the nighttime period was mediated by higher cardiac output (+2.6 ± 0.3 mL/min, [26%], P < 0.05) in association with lower peripheral resistance (−1.5 ± 0.3 mmHg/mL/min, [−13%] P < 0.05). The increased cardiac output during the nighttime was mainly mediated by increased heart rate (+80.0 ± 16.5 beats/min, [18%] P < 0.05), as stroke volume increased minimally at night (+1.6 ± 0.5 μL per beat, [6%] P < 0.05). These results indicate that in C57BL/6J mice, the 24 h pattern of blood pressure is hemodynamically mediated primarily by the 24 h pattern of cardiac output which is almost entirely determined by the 24 h pattern of heart rate. These findings suggest that the differences in blood pressure between nighttime and daytime are mainly driven by differences in heart rate which are strongly correlated with differences in locomotor activity.

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Section: Perspectivementioning

confidence: 90%

The 24 h pattern of arterial pressure in mice is determined mainly by heart rate-driven variation in cardiac output

2014

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“…The handling effect at time of dosing used was replicated from Snelder et al . ():

{HD}_{BP} = P_{BP} \cdot exp ([], - k_{HD} \cdot ((), t - t_{HD})) when t > t_{HD}

where P BP represents the magnitude of effect which decays over time from time of handling t HD , determined by rate constant k HD . An effect compartment was considered to account for delay between plasma concentrations and SBP changes.…”

Section: Methodsmentioning

confidence: 99%

Quantifying the relationship between inhibition of VEGF receptor 2, drug‐induced blood pressure elevation and hypertension

Collins

Gray

Bista

et al. 2018

British J Pharmacology

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BACKGROUND AND PURPOSESeveral anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors. EXPERIMENTAL APPROACHPorcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC 50 for VEGFR-2 phosphorylation. These IC 50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of allgrade hypertension. Unbound average plasma concentration (C av,u ) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic-pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments. KEY RESULTSAll-grade hypertension was predominantly observed when the C av,u was >0.1-fold of the VEGFR-2 (PAE) IC 50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mmHg was observed only when the C av,u was >0.1-fold of the VEGFR-2 (PAE) IC 50 . CONCLUSIONS AND IMPLICATIONSTaken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR-2 inhibition, and a margin of >10-fold between VEGFR-2 IC 50 and C av,u appears to confer a minimal risk of hypertension. AbbreviationsAUC 0-24 , the area under the plasma drug concentration-time curve calculated over 24

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“…Equally important to understanding a compound's efficacy is mitigation of a compound's known toxicity risks, and there are multiple examples of QSP models developed to predict hepatic, cardiac, renal,and gastrointestinal toxicity ( Table ). These models can be extremely useful early in the drug discovery process by helping teams predict and mitigate potential risks of the toxicity associated with molecules.…”

Section: Impactmentioning

confidence: 99%

Applications of Quantitative Systems Pharmacology in Model‐Informed Drug Discovery: Perspective on Impact and Opportunities

Bradshaw

Spilker

Zang³

et al. 2019

CPT Pharmacom & Syst Pharma

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Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

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

Cited by 29 publications

References 43 publications

The 24 h pattern of arterial pressure in mice is determined mainly by heart rate-driven variation in cardiac output

The 24 h pattern of arterial pressure in mice is determined mainly by heart rate-driven variation in cardiac output

Quantifying the relationship between inhibition of VEGF receptor 2, drug‐induced blood pressure elevation and hypertension

Applications of Quantitative Systems Pharmacology in Model‐Informed Drug Discovery: Perspective on Impact and Opportunities

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