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. 2018 May;7(5):309-320.
doi: 10.1002/psp4.12288. Epub 2018 Apr 16.

Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations

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Free PMC article

Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations

Stefan Willmann et al. CPT Pharmacometrics Syst Pharmacol. .
Free PMC article

Abstract

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

Figures

Figure 1
Figure 1
(a) Visualization of estimated relative bioavailability function used in the integrated population pharmacokinetic model compared with the 10 mg dose (F = 1). Dots represent the doses used in the studies. Values indicate the number of patients who received each dose. (b) Visualization of the estimated effects of patient characteristic covariates on apparent clearance (CL/F) and apparent volume of distribution (V/F). Estimated effects are given as fold‐change compared with reference category, symbols represent point estimates in fold‐change, and bars represent the 95% confidence interval of the point estimate obtained via bootstrapping. For continuous covariates (CrCLtruncated, weight and age), low and high are defined as the 5th and 95th percentile of the covariate distribution of the analysis population, respectively. The effects in these groups are shown relative to the median of the respective distribution. AF, atrial fibrillation; CrCLtruncated, Tietz‐truncated creatinine clearance; CYP3A4, cytochrome P450 3A4; PGP, p‐glycoprotein; VTE‐P, venous thromboembolism prevention; VTE‐T, venous thromboembolism treatment.
Figure 2
Figure 2
(a) Observations vs. population predictions (PRED) and individual predictions (IPRED), for all studies. DV, dependent variable. (b) Prediction‐corrected visual predictive checks (VPCs) of the pooled dataset. The orange circles represent the prediction‐corrected observations; the black horizontal bars show the 5th percentiles, medians, and 95th percentiles of the prediction‐corrected observations within the binning interval; the widths of the horizontal bars represent the range between the 5th–95th percentiles of the sampling time points of the observations within the binning interval; the vertical black lines indicate the medians of the sampling times within the binning interval; the blue shaded area represents the 95% confidence band around the 5th and 95th percentiles of the prediction‐corrected simulations; the red shaded area represents the 95% confidence band around the median of the prediction‐corrected simulations; the values indicate the numbers of observations at each binning interval.
Figure 3
Figure 3
Conditionally weighted residuals (CWRES) vs. population predictions (PRED) and time after dose for all studies.
Figure 4
Figure 4
Simulation results (area under the plasma concentration–time curve from time 0–24 hours (AUC0–24) at steady state following rivaroxaban 20 mg (left‐hand graphs) and 15 mg once daily (right‐hand graphs)) for the subgroups* according to renal function (top row), age (middle row), and weight (bottom row) for the atrial fibrillation indication. Calculations were performed using analytical equations. Boxes show the 25th–75th percentiles; the horizontal line in the box indicates the median; the open rhombus in the box indicates the mean; the whiskers represent 1.5 × interquartile range. *Virtual subgroups were defined by age (adults, 18 to <65 years; elderly, 65 to ≤75 years; and very elderly, >75 years), renal function (normal, creatinine clearance (CrCL) >80 mL/min; mild renal impairment (RI), CrCL 50 to ≤ 80 mL/min; moderate RI, CrCL 30 to <50 mL/min; and severe RI, CrCL <30 mL/min) and body mass index (underweight, <18.5 kg/m2; normal weight; 18.5 to <25 kg/m2; overweight, 25 to <30 kg/m2; obese, 30 to <40 kg/m2; and morbidly obese ≥40 kg/m2).

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