Exposure-response analysis of drug-induced QT interval prolongation in telemetered monkeys for translational prediction to human

Komatsu, Ryuichi; Mizuno, Hiroshi; Ishizaka, Tomomichi; Ito, Akihito; Jikuzono, Tatsuya; Kakoi, Tadashi; Bando, Masahiro; Koga, Tadashi; Handa, Jun; Takahashi, Yukio; Kanno, Akihiro; Ozaki, Harushige; Chiba, Katsuyoshi

doi:10.1016/j.vascn.2019.106606

Cited by 30 publications

(63 citation statements)

References 57 publications

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“…(1.1-to 2.5-fold) to prior dog and NHP estimates. 7,26 Clinical slope comparisons are also similar, as our data are within 0.4-to 1.2-fold of human estimates. 22,25,40 Consortium data (Japanese Safety Pharmacology Society and the Japanese Society for Biopharmaceutical Statistics) suggested that an interspecies C-QTc slope factor of 10 (N=5 QT-positive; N=1 QT-negative) was an acceptable threshold for translational agreement.…”

Section: Accepted Articlesupporting

confidence: 84%

“…40 Slope analysis of the NHP data was consistent with prior evidence, and identical to recently published data in the same species. 7 Threshold concentrations predicting a 10 ms QTc prolongation (Tables 1 to 3) are also very close…”

Section: Accepted Articlementioning

confidence: 78%

“…50, 51 C-QTc slope comparisons in the same species ranged from 1.0-to 2.5-fold of published evidence (Table 3). 7,26 The challenges associated with QTc translation across species were previously highlighted by Ewart et al, 4 in a cross-company collaboration that sought to compare dog QTc responses with human QTc effects (phase 1 trials) for 113 novel drugs. Their analysis clearly demonstrated that the dog telemetry QTc assay had excellent negative predictive value (high specificity) for phase 1 findings.…”

Section: Accepted Articlementioning

confidence: 99%

“…The need for this cardiovascular safety core assay is described in the ICH S7B guideline. 1 The in vivo QTc assay has demonstrated high translational value for predicting QTc interval prolongation in humans [2][3][4][5][6][7] . In conjunction with the in vitro human ether-a-go-go K+ current (hERG) assay, a negative signal in the in vivo QTc assay lowers the probability of clinical ventricular arrhythmia risk for a new drug product 8 .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Accepted Articlesupporting

confidence: 84%

Section: Accepted Articlementioning

confidence: 78%

Section: Accepted Articlementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…For example, independent analyses have characterized the ability of these assays to detect compounds likely to be TQT positive 5,6,42,43 or have enhanced TdP risk. [44][45][46][47][48][49] The translation of QTc interval prolongation specifically from large animals to the clinic has also been extensively evaluated (dog, 20,50,51 nonhuman primate, 46,52 and multiple species 53 ) and their predictive value demonstrated, which was unknown 15 years ago when ICH S7B was introduced. Within our companies, these core assays, in concert with early-stage or exploratory screening assays 54 ( Figure 1) have directly driven the design and selection of molecules with low hERG potency and reduced the clinical likelihood of QTc prolongation and TdP risk.…”

Section: Linking Ich S7b and Ich E14: Acknowledging The Predictive Vamentioning

confidence: 99%

Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective

Vargas

Rolf

Wisialowski

et al. 2020

Clin Pharma and Therapeutics

Self Cite

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Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based “double‐negative” nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

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Results from a Joined Prospective Study to Evaluate the Sensitivity of the In Vivo Dog QT Assay in Line with the ICH E14/S7B Q&A Best Practices

Bétat,

Delaunois,

Delpy

et al. 2024

Clin Pharma and Therapeutics

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The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non‐rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure–response analysis was performed, as done in clinical practice. By‐timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic Cmax. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration‐QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug‐induced QTc prolongation in humans as a key pillar of the integrated risk assessment.

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Exposure-response analysis of drug-induced QT interval prolongation in telemetered monkeys for translational prediction to human

Cited by 30 publications

References 57 publications

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

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

Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective

Results from a Joined Prospective Study to Evaluate the Sensitivity of the In Vivo Dog QT Assay in Line with the ICH E14/S7B Q&A Best Practices

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