Preclinical to Clinical Translation of Hemodynamic Effects in Cardiovascular Safety Pharmacology Studies

Bhatt, Siddhartha; Northcott, Carrie A.; Wisialowski, Todd; Li, Dingzhou; Steidl-Nichols, Jill

doi:10.1093/toxsci/kfz035

Cited by 16 publications

(6 citation statements)

References 26 publications

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“…In contrast, the Bhatt et al. paper describes translation experience based on datasets that are much more consistent 62 . In this study, the rat CV model showed good concordance with BP and HR changes in large animal (LA), such as the dog and monkey.…”

Section: Discussionmentioning

confidence: 65%

A tutorial for model‐based evaluation and translation of cardiovascular safety in preclinical trials

Kulesh,

Vasyutin,

Volkova

et al. 2023

CPT Pharmacom & Syst Pharma

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Assessment of drug‐induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug related unintended CV effects in the preclinical stage is necessary for first‐in‐human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, non‐clinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model‐based approaches including empirical pharmacokinetic‐toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of non‐clinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model‐based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.

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Section: Discussionmentioning

confidence: 65%

A tutorial for model‐based evaluation and translation of cardiovascular safety in preclinical trials

Kulesh,

Vasyutin,

Volkova

et al. 2023

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

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“…Undesired CV effects are a major cause of drug attrition during preclinical and clinical development. Therefore, blood pressure is a primary parameter collected in CV safety pharmacology studies (Bhatt et al, 2019 ; Laverty et al, 2011 ; U.S. Department of Health and Human Services Food and Drug Administration, 2001 ). Typically, changes in blood pressure are reported as deviations in systolic, diastolic, and derived mean pressures.…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of canine‐specific computational models to predict pulsatile arterial hemodynamics and ventricular‐arterial coupling

Hotek,

Chirinos,

Detwiler

et al. 2023

Physiological Reports

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Pulsatile hemodynamics analyses provide important information about the ventricular‐arterial system which cannot be inferred by standard blood pressure measurements. Pulse wave analysis (PWA), wave separation analysis (WSA), and wave power analysis (WPA) characterize arterial hemodynamics with limited preclinical applications. Integrating these tools into preclinical testing may enhance understanding of disease or therapeutic effects on cardiovascular function. We used a canine rapid ventricular pacing (RVP) heart failure model to: (1) Characterize hemodynamics in response to RVP and (2) assess analyses from flow waveforms synthesized from pressure compared to those derived from measured flow. Female canines (n = 7) were instrumented with thoracic aortic pressure transducers, ventricular pacing leads, and an ascending aortic flow probe. Data were collected at baseline, 1 week, and 1 month after RVP onset. RVP progressively reduced stroke volume (SV), the PWA SV estimator, and WSA and WPA pulsatility and wave reflection indices. Indices derived from synthesized flow exhibited similar directional changes and high concordance with measured flow calculations. Our data demonstrate the value of analytical hemodynamic methods to gain deeper insight into cardiovascular function in preclinical models. These approaches can provide complementary value to standard endpoints in evaluating potential effects of pharmaceutical agents intended for human use.

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“…6,14 Cardiovascular safety testing is an important component of the battery of risk evaluation strategies employed in any drug development process. 15 ICH S7A and S7B guidelines direct on procedures employed for assessment of drug effects on hemodynamic parameters along with central nervous system (CNS) and respiratory assessment and assessment of proarrhythmic risk of drugs (QTc prolongation and drug-induced arrhythmias). [15][16][17] Drug-induced QT prolongation is a major cardiovascular concern in the safety assessment of novel drugs and regulatory authorities worldwide warrant a thorough pro-arrhythmic risk evaluation of test molecules.…”

Section: Introductionmentioning

confidence: 99%

“…15 ICH S7A and S7B guidelines direct on procedures employed for assessment of drug effects on hemodynamic parameters along with central nervous system (CNS) and respiratory assessment and assessment of proarrhythmic risk of drugs (QTc prolongation and drug-induced arrhythmias). [15][16][17] Drug-induced QT prolongation is a major cardiovascular concern in the safety assessment of novel drugs and regulatory authorities worldwide warrant a thorough pro-arrhythmic risk evaluation of test molecules. 18,19 Rarely, drugs trigger different arrhythmias such as bradyarrhythmia, atrial fibrillation/flutter, atrial tachycardia, monomorphic ventricular tachycardia, Brugada syndrome, and Torsades de Pointes (TdP).…”

Section: Introductionmentioning

confidence: 99%

A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys (Macaca mulatta)

Bhatt,

Shah,

Patel

et al. 2023

Int J Toxicol

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Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.

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Preclinical to Clinical Translation of Hemodynamic Effects in Cardiovascular Safety Pharmacology Studies

Cited by 16 publications

References 26 publications

A tutorial for model‐based evaluation and translation of cardiovascular safety in preclinical trials

A tutorial for model‐based evaluation and translation of cardiovascular safety in preclinical trials

Development and characterization of canine‐specific computational models to predict pulsatile arterial hemodynamics and ventricular‐arterial coupling

A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys (Macaca mulatta)

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