Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP)

Kremer, John J.; Bills, Andrew J.; Hanke, Nathanael J.; Chen, Hepei; Meier, William A.; Osinski, Mark A.; Foley, C. Michael

doi:10.1016/j.vascn.2015.05.008

Cited by 13 publications

(4 citation statements)

References 33 publications

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“…The exposure levels were dose-dependent and measurable between 7 and 7.5 h post-dose in the beagles that received etilefrine, sotalol, and hydralazine. Male and female beagles exposed to 10 mg/kg of etilefrine showed varying concentrations (169 vs. 268 ng/mL or 69%), with generally minor differences observed ( Kremer et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

The relationship between gender and pharmacology

Younes

2024

Current Research in Pharmacology and Drug Discovery

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Section: Resultsmentioning

confidence: 99%

The relationship between gender and pharmacology

Younes

2024

Current Research in Pharmacology and Drug Discovery

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“…The QT interval was corrected for heart rate changes for each animal using a linear model, dog QTcI = QT – Individual Animal Correction Factor (IACF) × (HR – 75) or NHP QTcI = QT + IACF × (750 – interval between successive R waves (RR)) where the variables and linear regression slope were established on an species/individual animal‐specific basis using QT and HR or RR (used to derive HR) data points from 1‐min means collected during the vehicle collection. 2 , 18 , 36 Vehicle‐corrected QTc (ΔQTc) were calculated by subtracting vehicle QTc values from each animal at each timepoint and dose level. ΔQTc values were further corrected by subtracting baseline values from each animal to obtain ΔΔQTc values used for C‐QTc analysis.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

Chui

Baublits

Chandra

et al. 2021

Clinical Translational Sci

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The in vivo QTc assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in ICH S7B guideline. The typical telemetry study involves a dose-response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure, e.g. concentration-QTc (C-QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non-human primate (NHP) QTc assays. For timepoint analysis, a conventional design using 8 animals (8x4CO) to detect moxifloxacin-induced QTc prolongation was compared to a PK/PD design in a subset (N=4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms.Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C-QTc slope values were 0.7-(dog) and 1.2-(NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C-QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

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“…The exposure levels were dose-dependent and quantifiable between 7 and 7.5 h post-dose in the dogs that were given etilefrine, sotalol, and hydralazine. The male and female beagles exposed to 10 mg/kg of etilefrine experienced different concentrations (169 vs. 268 ng/mL or 69%), but generally, there were only small differences [ 130 ].…”

Section: Excursus On Preclinical Pharmacology Research: Sex Disaggreg...mentioning

confidence: 99%

Evaluation of Sex Differences in Preclinical Pharmacology Research: How Far Is Left to Go?

Allegra,

Chiara,

Di Grazia

et al. 2023

Pharmaceuticals

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Until the last quarter of the 20th century, sex was not recognized as a variable in health research, nor was it believed to be a factor that could affect health and illness. Researchers preferred studying male models for a variety of reasons, such as simplicity, lower costs, hormone confounding effects, and fear of liability from perinatal exposure in case of pregnancy. Equitable representation is imperative for determining the safety, effectiveness, and tolerance of therapeutic agents for all consumers. Decades of female models’ underrepresentation in preclinical studies has resulted in inequality in the understanding, diagnosis, and treatment of disease between the sexes. Sex bias has been highlighted as one of the contributing factors to the poor translation and replicability of preclinical research. There have been multiple calls for action, and the inclusion of sex as a biological variable is increasingly supported. However, although there has been substantial progress in the efforts to include more female models in preclinical studies, disparities today remain. In the present review, we consider the current standard practice of the preclinical research setting, why the sex bias exists, why there is the need to include female models, and what risks may arise from continuing this exclusion from experimental design.

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Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP)

Cited by 13 publications

References 33 publications

The relationship between gender and pharmacology

The relationship between gender and pharmacology

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

Evaluation of Sex Differences in Preclinical Pharmacology Research: How Far Is Left to Go?

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