Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations

Willmann, Stefan; Zhang, Liping; Frede, Matthias; Kubitza, Dagmar; Mueck, Wolfgang; Schmidt, Stephan; Solms, Alexander; Yan, Xiaoyu; Garmann, Dirk

doi:10.1002/psp4.12288

Cited by 58 publications

(164 citation statements)

References 36 publications

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“…Individual rivaroxaban exposure estimates are essential to enable large‐scale ER analyses to be performed in several indications. An integrated popPK model based on phase II studies and a small subset of patients from a phase III trial was initially developed to estimate rivaroxaban exposure for the phase III population based on dose and patient characteristics . However, because this covariate‐only popPK model cannot incorporate any additional IIV (in the absence of PK data), the distribution of the exposure estimates is restricted, and this negatively impacts the ability to establish ER relationships in subsequent analyses.…”

Section: Discussionmentioning

confidence: 99%

“…The η approach was similar to the popPK approach used in the presence of PK sampling . Using the previously developed popPK model and the linear relationship between measured PT and PK samples ( Figures and ), PK estimates were derived based on measured PT values only. These post hoc PK estimates were used to derive the steady‐state exposure metrics of interest.…”

Section: Methodsmentioning

confidence: 99%

“…Covariate information, including demographic characteristics and use of relevant comedications, was considered for the included patients, as reported previously for the integrated popPK model . Age and sex were known for each of these patients.…”

Section: Methodsmentioning

confidence: 99%

“…In the case of a missing covariate, this value was imputed using the median value of the respective age and sex group of the relevant study. For patients taking comedications, constant comedication factors for the study period were assumed and derived as described previously . No time‐changing covariates were considered in the popPK model because a constant dose was assumed and exposure metrics were time invariant …”

Section: Methodsmentioning

confidence: 99%

“…Previously, an integrated population PK (popPK) model including a covariate analysis was developed to predict rivaroxaban exposure across indications based on dose and patient characteristics . The model used pooled data from 4,918 patients in seven phase II and III clinical trials and was found to provide reliable rivaroxaban exposure estimates across all approved indications .…”

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confidence: 99%

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Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling

Solms

Frede

Berkowitz

et al. 2019

CPT Pharmacom & Syst Pharma

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Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure–response analyses, the aim of the present study was to investigate the use of PT‐adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT‐adjustment approaches were established using time‐matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT‐adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate‐only exposure estimates.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling

Solms

Frede

Berkowitz

et al. 2019

CPT Pharmacom & Syst Pharma

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Population Pharmacokinetic Models for Direct Oral Anticoagulants: A Systematic Review and Clinical Appraisal Using Exposure Simulation

Terrier

Gaspar

Guidi

et al. 2022

Clin Pharma and Therapeutics

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Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular attention. Population pharmacokinetic (PopPK) analyses can help in identifying such factors while providing predictive models. The main aim of the present study was to identify all the PopPK models to date for the four most frequently used DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban). The secondary aim was to use these models to simulate different DOAC plasma concentration–time profiles in relevant clinical scenarios. The results of our model‐based simulations confirm the clinical relevance of the known major factors influencing DOAC exposure and support the current approved dose adaptation, at least for atrial fibrillation. They also highlight how the accumulation of covariates, not currently considered for dose adaptation due to their seemingly minor influence on DOAC exposure, lead to supratherapeutic blood concentrations and could thus enhance the risk of major bleeding. The present results therefore question DOAC dose adaptation in the presence of these covariates, such as drug–drug interaction or genotypes, alongside the known existing covariates. As the overall effect of accumulation of several covariates could be difficult to apprehend for the clinicians, PopPK modeling could represent an interesting approach for informed precision dosing and to improve personalized prescription of DOACs.

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Exposure Matching‐Based Pediatric Dose Selection for Drugs with Renal Excretion – Lessons Learned from Pediatric Development of Direct Oral Anticoagulants

Zou,

Leil

2024

Clin Pharma and Therapeutics

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The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age‐dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age‐related differences in disease and response to treatment; (2) consideration of age‐related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub‐populations.

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Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations

Cited by 58 publications

References 36 publications

Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling

Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling

Population Pharmacokinetic Models for Direct Oral Anticoagulants: A Systematic Review and Clinical Appraisal Using Exposure Simulation

Exposure Matching‐Based Pediatric Dose Selection for Drugs with Renal Excretion – Lessons Learned from Pediatric Development of Direct Oral Anticoagulants

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