Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations

Author:

Leven Cyril12ORCID,Ménard Pauline3,Gouin-Thibault Isabelle45,Ballerie Alice56,Lacut Karine17,Ollier Edouard8,Théreaux Jérémie19

Affiliation:

1. Inserm, UMR 1304 (GETBO), Western Brittany Thrombosis Study Group, Western Brittany University, 29238 Brest, France

2. Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, 29200 Brest, France

3. Department of Hematology, Brest University Hospital, 29200 Brest, France

4. Hematology Laboratory, Rennes University Hospital, 35000 Rennes, France

5. Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Université de Rennes, 35708 Rennes, France

6. Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, 35000 Rennes, France

7. Internal Medicine, Vascular Medicine and Pneumology Department, Brest University Hospital, 29200 Brest, France

8. SAINBIOSE, INSERM U1059, Université de Lyon, 69621 Saint-Etienne, France

9. Department of General, Digestive and Metabolic Surgery, Brest University Hospital, 29200 Brest, France

Abstract

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

Publisher

MDPI AG

Subject

Pharmaceutical Science

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