Model-Based Evaluation of Exenatide Effects on the QT Interval in Healthy Subjects Following Continuous IV Infusion

Abstract

Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations. The final model includes stimulatory drug effects on glucose elimination and HR perturbations. The targeted and constant exenatide plasma concentrations (>200 pg/mL), via intravenous infusions at multiple dose levels, resulted in significant inhibition of glucose concentrations. The exenatide concentration associated with 50% of the stimulation of HR production was 584 pg/mL. After accounting for exenatide effects on glucose and HR, no additional drug effects were required to explain observed changes in the QT interval. Resulting glucose, HR, and QT profiles at all exenatide concentrations were adequately described. For therapeutic agents that alter glycemic conditions, particularly those that alter postprandial glucose, the QT interval cannot be directly compared to that with placebo without first accounting for confounding factors (eg, glucose) either through mathematical modeling or careful consideration of mealtime placement in the study design.

Keywords: QT interval; glucose; heart rate; mathematical modeling.

Figure 1

Study design schema. The overall study design is shown (top row), along with the PK/PD sampling schemes and meal content (bottom rows). Cohorts A, B, and C are sequential cohorts evaluating different exenatide infusion rates. Timing of the breakfast meal relative to the PD assessment points is also shown. Br, breakfast; Dn, dinner; ECG, electrocardiogram; Lu, lunch; PD, pharmacodynamic; PK, pharmacokinetic.

Figure 2

Pharmacokinetic and pharmacodynamic model diagram. Symbols and model equations are defined in the PK/PD Modeling in the Methods section.

Figure 3

Temporal profiles of median pharmacodynamic endpoints stratified by day. Median glucose concentrations (left panel) and HR profiles (right panel) are shown as a function of time and stratified by day. bpm, beats per minute; HR, heart rate.

Figure 4

Final pharmacokinetic model internal qualification. Visual predictive check of the pharmacokinetic profiles is shown across the 3‐day infusion. Symbols represent individual observed data, the dashed line is the 50th percentile of the observed data, and the solid line is the median of the model simulations. The shaded area defines the 5th to 95th percentiles of 1000 simulations. The inset figure shows 2 representative subjects (A and B) with symbols representing observed values, solid lines representing the population mean predicted concentration, and dashed lines representing individual predicted concentrations.

Figure 5

Final pharmacodynamic model internal qualification. Visual predictive checks are shown for glucose, HR, and QT. Symbols represent individual observed data, dashed lines represent the 50th percentiles of the observed data, and solid lines represent medians of the simulations. Shaded areas define the 5th to 95th percentiles of 1000 simulations. bpm, beats per minute; HR, heart rate.

Figure 6

Simulated change in heart rate‐corrected QT interval (mQTc) from the premeal time point stratified by treatment (exenatide concentration of 200 pg/mL) and placebo. Figures represent the median individual prediction mQTc following exenatide treatment (triangles) and placebo (circles) following a breakfast meal of 99 g carbohydrates at 6 am for a subject with a baseline glucose of 92.8 mg/dL, baseline heart rate of 64.1 beats/min, and a baseline QT interval of 393 milliseconds.