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

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Feb 25

PMID 36839986

Authors

Cyril Leven

Pauline Menard

Isabelle Gouin-Thibault

Alice Ballerie

Karine Lacut

Edouard Ollier

Jeremie Thereaux

Affiliations

Soon will be listed here.

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.

Citing Articles

Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis.

Konecki C, Lipman M, Mavrakanas T, Djerada Z Clin Pharmacokinet. 2025; 64(2):307-321.

PMID: 39853633 DOI: 10.1007/s40262-025-01476-6.

References

Zhang H, Sheng C, Liu L, Luo B, Fu Q, Zhao Q . Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus. Br J Clin Pharmacol. 2019; 85(4):746-761. PMC: 6422729. DOI: 10.1111/bcp.13850. View

Martin K, Beyer-Westendorf J, Davidson B, Huisman M, Sandset P, Moll S . Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016; 14(6):1308-13. PMC: 4936273. DOI: 10.1111/jth.13323. View

Morrish G, Pai M, Green B . The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol. 2011; 7(6):697-706. DOI: 10.1517/17425255.2011.570331. View

Ballerie A, Nguyen Van R, Lacut K, Galinat H, Rousseau C, Pontis A . Apixaban and rivaroxaban in obese patients treated for venous thromboembolism: Drug levels and clinical outcomes. Thromb Res. 2021; 208:39-44. DOI: 10.1016/j.thromres.2021.10.009. View

Zdovc J, Petre M, Pislar M, Repnik K, Mrhar A, Vogrin M . Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study. Eur J Clin Pharmacol. 2019; 75(6):817-824. DOI: 10.1007/s00228-019-02639-8. View

Suzuki S, Yamashita T, Kasai H, Otsuka T, Sagara K . An analysis on distribution and inter-relationships of biomarkers under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (CVI ARO 1). Drug Metab Pharmacokinet. 2018; 33(4):188-193. DOI: 10.1016/j.dmpk.2018.02.002. View

Gallus S, Lugo A, Murisic B, Bosetti C, Boffetta P, La Vecchia C . Overweight and obesity in 16 European countries. Eur J Nutr. 2014; 54(5):679-89. DOI: 10.1007/s00394-014-0746-4. View

Leven C, Coste A, Mane C . Free and Open-Source Posologyr Software for Bayesian Dose Individualization: An Extensive Validation on Simulated Data. Pharmaceutics. 2022; 14(2). PMC: 8879752. DOI: 10.3390/pharmaceutics14020442. View

Smit C, de Hoogd S, Bruggemann R, Knibbe C . Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. Expert Opin Drug Metab Toxicol. 2018; 14(3):275-285. DOI: 10.1080/17425255.2018.1440287. View

10.

Mueck W, Borris L, Dahl O, Haas S, Huisman M, Kakkar A . Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008; 100(3):453-61. View

11.

Hanafin P, Nation R, Scheetz M, Zavascki A, Sandri A, Kwa A . Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients. CPT Pharmacometrics Syst Pharmacol. 2021; 10(12):1525-1537. PMC: 8674003. DOI: 10.1002/psp4.12720. View

12.

Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T . Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation. Br J Clin Pharmacol. 2018; 84(6):1301-1312. PMC: 5980466. DOI: 10.1111/bcp.13561. View

13.

Jain R, Chung S, Jain L, Khurana M, Lau S, Lee J . Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther. 2011; 90(1):77-89. DOI: 10.1038/clpt.2011.104. View

14.

Mueck W, Lensing A, Agnelli G, Decousus H, Prandoni P, Misselwitz F . Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011; 50(10):675-86. DOI: 10.2165/11595320-000000000-00000. View

15.

Han P, Duffull S, Kirkpatrick C, Green B . Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther. 2007; 82(5):505-8. DOI: 10.1038/sj.clpt.6100381. View

16.

Xu X, Moore K, Burton P, Stuyckens K, Mueck W, Rossenu S . Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol. 2012; 74(1):86-97. PMC: 3394132. DOI: 10.1111/j.1365-2125.2012.04181.x. View

17.

Gosselin R, Adcock D, Bates S, Douxfils J, Favaloro E, Gouin-Thibault I . International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost. 2018; 118(3):437-450. DOI: 10.1055/s-0038-1627480. View

18.

Liu X, Zhang Y, Ding H, Yan M, Jiao Z, Zhong M . Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation. Acta Pharmacol Sin. 2022; 43(10):2723-2734. PMC: 9525623. DOI: 10.1038/s41401-022-00892-9. View

19.

Kearon C, Ageno W, Cannegieter S, Cosmi B, Geersing G, Kyrle P . Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost. 2016; 14(7):1480-3. DOI: 10.1111/jth.13336. View

20.

Beal S . Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2002; 28(5):481-504. DOI: 10.1023/a:1012299115260. View