Effect of Amiodarone on Apixaban Exposure in Patients after Cardiac Surgery—A Population Pharmacokinetic Study

Figures

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  Fig. 1. Prediction-corrected visual predictive check of the population pharmacokinetic model of apixaban; 10 th to 90 th percentile (dashed lines) and median (solid line) and corresponding 95% confidence intervals of the model prediction. N = 500 simulations

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  Fig. 2. Population predictions (PRED, left) or individual predictions (IPRED, right) versus observed apixaban concentration (DV)

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  Fig. 3. Time after dose (left) or individual predictions (right) versus normalized prediction distribution error (NPDE). The dashed lines indicate the expected 2.5 th, 50 th, and 97.5 th percentile

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  Fig. 4. Covariate relationships of apixaban CL/F versus amiodarone comedication (left) and CrCL (right). Solid line (right): estimated covariate relationship. P-value from comparison of post hoc estimates of CL/F using a two-sided t-test

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  Fig. 5. Apixaban Cmin for the labeled doses of 5 mg b.i.d. or 2.5 mg b.i.d. in 1000 simulated individuals with differing CrCL with (blue boxes) or without amiodarone (green boxes). Italic numbers above boxes show the proportion of profiles with Cmin > 230 ng/mL of the respective scenario. Italic numbers below boxes show the proportion of profiles with Cmin < 34 ng/mL. Dashed lines indicate an expected Cmin range of 34–230 ng/mL (5 th, 95 th percentile) [13, 28]. b.i.d. twice daily, Cmin trough concentrations, CrCL creatinine clearance

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  Fig. 6. Apixaban Cmin distribution of the labeled dose (green boxes) and a potential dosing strategy for amiodarone comedication (blue boxes) at different CrCL ranges. Italic numbers above boxes show the proportion of profiles with Cmin > 230 ng/mL of the respective scenario. Italic numbers below boxes show the proportion of profiles with Cmin < 34 ng/mL. b.i.d. twice daily, Cmin trough concentrations, CrCL creatinine clearance

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  Fig. 7. Predicted apixaban concentrations over 48 h using the available strengths of 2.5 mg and 5 mg b.i.d. (simulated for 1000 individuals). Green shaded plots show the labeled dose. Blue shaded plots show the proposed dosing scheme with amiodarone comedication. Dashed lines represent the 5 th and 95 th percentile; the solid line represents the median. The dotted line indicates the bleeding threshold of Cmin: 230 ng/mL apixaban [18, 27]. b.i.d. twice daily, CrCL creatinine clearance