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

Figures

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  FIGURE 1. Sequential workflow of model‐based telemetry data analyses.

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  FIGURE 2. Rat telemetry data visualization. (a) Semilogarithmic plot of plasma PK after single dose administered by oral gavage; dots with error bars—mean ± SE. (b) PK profiles stratified by dose; dots and thin lines—individual data, thick lines—mean trends. (c) Dose‐adjusted AUC and C max versus dose; dots with error bars—mean ± SE, dashed blue line—linear regression. Change over time in heart rate (d), baseline‐adjusted (e), baseline‐ and placebo‐adjusted (f); dots with error bars—mean ± SE. AUC, area under the curve; CFB, change from baseline; CFP, change from placebo; C max, maximum plasma concentration; PK, pharmacokinetic.

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  FIGURE 3. Time profiles of observed and predicted PK in rats. (a) PK model with saturable absorption; dots with error bars—mean ± SE, curves—model predictions. (b) PK model with random effects; dots—individual observations, curves—individual predictions, ID—animal identifier. (c) PK model with study as a covariate on clearance and intercompartmental flux; dots with error bars—mean ± SE, curves—model predictions. PK, pharmacokinetic.

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  FIGURE 4. Observed and predicted heart rate in rats (a–c) and dogs (d–e) in control arms. (a) Single cosine function, different magnitude for each handling effect without physiological threshold. (b) Same as panel a, with physiological threshold. (c) Same as panel a, with two cosine functions. (d) Single cosine function, same magnitude for each handling effect without physiological threshold. (e) Same as panel d, no handling effects. Dots with error bars—mean ± SE, curves—model predictions.

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  FIGURE 5. Animal toxicodynamic data patterns and associated modeling solutions. (a) Observed and predicted response in placebo and treated cohorts with handling effect excluded from the drug effect model; dots with error bars—mean ± SE, curves—model predictions. (b) Hysteresis plot for mean baseline‐ and placebo‐adjusted heart rate against the simulated PK; error bars—95% CI. Change over time in baseline‐ and placebo‐adjusted heart rate against the simulated PK; dots with error bars—observed mean heart rate ± SE, for (c) solid curve—predicted PK in central compartment, dashed curve—predicted PK in biophase compartment, for (d) solid curve—predicted PK without adaptation function, dashed curve—predicted PK with adaptation function. CFP, change from placebo; CI, confidence interval; PK, pharmacokinetic.

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  FIGURE 6. Schematic representation of the animal‐to‐human translation workflow. (a) Animal model schematics. (b) Human model schematics. (c) The upper limit of 95% prediction interval for the absolute change from baseline in human heart rate under treatment at steady state; curves—model predictions. (d) Exposure‐response plot for the relative change from baseline in human heart rate; solid curve with shaded area—predicted mean with 95% prediction interval, red dashed lines—exposure corresponding to the 97.5% percentile of the C max prediction distribution at selected doses, shaded region—exposure exceeding maximum concentrations observed in animals (i.e., extrapolation). CFB, change from baseline.