Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study

Figures

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  Figure 1. Body weight–adjusted dosing table proposed for UNIVERSE (daily dose, administered twice daily), comparison of PBPK‐predicted rivaroxaban exposure (AUC24h, steady state), and steady‐state plasma concentration‐time profile of rivaroxaban predicted for post‐Fontan patients aged 2‐8 years (green) in comparison to healthy pediatric(12) and/or adult(12) reference population for the proposed dosing regimen. AUC24h, area under the plasma concentration‐time curve to 24 hours. BID, twice daily; OD, once daily.

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  Figure 2. Comparison of rivaroxaban exposure in UNIVERSE study with the adult reference study ODIXa‐HIP‐OD and with the simulated pediatric range using the EINSTEIN‐Jr population PK model and the UNIVERSE dose regimen. Green solid lines represent adult 10‐mg once‐daily reference median exposure metrics (A, AUC24h,ss; B, Cmax,ss; C, Ctrough,ss); black solid lines represent simulated pediatric median at 10 mg once daily equivalent exposure metrics; black solid triangles (red solid dots) represent individual exposure metrics prediction for part B (part A) of the UNIVERSE study; gray shaded area represents 2.5th and 97.5th percentile range of adult 10‐mg once‐daily reference; solid shaded area represents simulated pediatric 2.5th and 97.5th prediction interval at 10 mg once daily equivalent. 2.5th‐97.5th percentile exposure ranges of the adult reference are AUC24h,ss: 820–3216 μg • h/L; Cmax,ss: 70.2–215.8 μg/L; Ctrough,ss: 3.55–52.0 μg/L. AUC24h,ss, area under the plasma concentration–time curve to 24 hours at steady state; Cmax,ss, postdose maximum concentration at steady state; Ctrough,ss, predose concentrations at steady state; PK, pharmacokinetics.

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  Figure 3. Prothrombin time (PT) vs plasma rivaroxaban concentrations: comparison between the UNIVERSE study and the adult reference in studies ODIXa‐HIP2 and ODIXa‐KNEE. The solid blue line represents the median of the adult reference; the blue dashed lines represent the 99% prediction range of the adult reference.

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  Figure 4. Activated partial thromboplastin time (aPTT) vs rivaroxaban concentrations: comparison between the UNIVERSE study and the adult reference studies ODIXa‐HIP2 and ODIXa‐KNEE. The solid blue line represents the median of adult reference; the blue dashed lines represent 99% prediction range of the adult reference.

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  Figure 5. Anti–factor Xa activity as a function of plasma rivaroxaban concentrations in the UNIVERSE study. The solid blue line represents the median of model prediction; the red dashed lines represent the 95% prediction interval. Regression line: y = −3.14 + 0.885*x; R 2 = 0.901.

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  Figure 6. Exposure‐thrombosis event relationship of rivaroxaban in the UNIVERSE study. Individual values are provided where n = 1. The solid line in the box is the median. The boundaries of the box represent the 25th and 75th percentiles. The whiskers are the nearest values within 1.5 times the interquartile range below and above the 25th and 75th percentiles, respectively. AUC24h,ss, area under the plasma concentration–time curve to 24 hours at steady state; Cmax,ss, postdose maximum concentration at steady state; Ctrough,ss, predose concentrations at steady state.

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  Figure 7. Exposure‐bleeding events relationship of rivaroxaban in the UNIVERSE study. All bleeding includes the 3 bleeding categories: major, trivial, and CRNM. The solid line in the box is the median. The boundaries of the box represent the 25th and 75th percentiles. The whiskers are the nearest values within 1.5 times the interquartile range below and above the 25th and 75th percentiles, respectively. AUC24h,ss, area under the plasma concentration–time curve to 24 hours at steady state; Cmax,ss, postdose maximum concentration at steady state; CRNM, clinically relevant nonmajor bleeding; Ctrough,ss, predose concentrations at steady state.