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Population pharmacokinetics of rivaroxaban in Chinese deep vein thrombosis patients and the exposure simulation for dosing recommendation

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Abstract

This study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban and establish a model-based dosing guideline tailored to Chinese patients with deep vein thrombosis (DVT). A nonlinear mixed-effects modeling approach was employed using Phoenix NLME 7.0 software to construct the PPK model for rivaroxaban. The PK of rivaroxaban was adequately characterized through a one-compartment model. Monte Carlo simulations were employed to formulate dosing guidelines applicable to different patient subgroups. Data from 60 Chinese DVT patients yielded 217 rivaroxaban plasma concentrations for analysis. The apparent clearance (CL/F) of rivaroxaban was found to be significantly influenced by the estimated glomerular filtration rate (eGFR), identified as a major covariate. Based on Monte Carlo simulations, for the acute DVT treatment, a regimen of 15 mg, 10 mg, or 5 mg twice daily was associated with the highest total probability target attainment (PTAtotal) in patients with normal, mildly impaired, or moderately impaired renal function, respectively. For the continued DVT treatment, a regimen of 20 mg, 15 mg, or 5 mg once daily exhibited the maximum PTAtotal in patients with normal, mildly impaired, or moderately impaired renal function, respectively. The recommendation label dose achieved the PK target in those with normal renal function. However, for patients with mild or moderate renal impairment, dose adjustments below the label recommendation might be necessary. The PPK model associated CL/F with the covariate eGFR. Utilizing the PPK model, a dosage regimen table was constructed to offer tailored dosing recommendations for Chinese DVT patients.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  • Agnelli G, Gallus A, Goldhaber SZ et al (2007) Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939) - the ODIXa-DVT (oral direct factor Xa inhibitor BAY 59–7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation 116(2):180–187

    Article  PubMed  CAS  Google Scholar 

  • Bouget J, Balusson F, Maignan M et al (2020) Major bleeding risk associated with oral anticoagulant in real clinical practice. A multicentre 3-year period population-based prospective cohort study. Br J Clin Pharmacol 86(12):2519–2529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Buller HR, Lensing AWA, Prins MH et al (2008) A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood 112(6):2242–2247

    Article  PubMed  CAS  Google Scholar 

  • Derogis PBM, Sanches LR, de Aranda VF et al (2017) Determination of rivaroxaban in patient’s plasma samples by anti-Xa chromogenic test associated to high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). PLoS ONE 12(2):e0171272

    Article  PubMed  PubMed Central  Google Scholar 

  • Eriksson BI, Borris L, Dahl OE et al (2006) Oral, direct factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 4(1):121–128

    Article  PubMed  CAS  Google Scholar 

  • Girgis IG, Patel MR, Peters GR et al (2014) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol 54(8):917–927

    Article  PubMed  CAS  Google Scholar 

  • Gong IY, Kim RB (2013) Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 29(7):S24–S33

    Article  PubMed  Google Scholar 

  • Goto E, Horinaka S, Ishimitsu T et al (2020) Factor Xa inhibitors in clinical practice: comparison of pharmacokinetic profiles. Drug Metab Pharmacokinet 35(1):151–159

    Article  PubMed  CAS  Google Scholar 

  • Halperin JL, Hankey GJ, Wojdyla DM et al (2014) Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 130(2):138–146

    Article  PubMed  CAS  Google Scholar 

  • Johnson JA (1997) Influence of race or ethnicity on pharmacokinetics of drugs. J Pharm Sci 86(12):1328–1333

    Article  PubMed  CAS  Google Scholar 

  • Kaneko M, Tanigawa T, Hashizume K et al (2013) Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients. Drug Metab Pharmacokinet 28(4):321–331

    Article  PubMed  CAS  Google Scholar 

  • Kong XL, Ma YC, Chen JH et al (2013) Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating glomerular filtration rate in the Chinese population. Nephrol Dial Transplant 28(3):641–651

    Article  PubMed  CAS  Google Scholar 

  • Kubitza D, Becka M, Mueck W et al (2010) Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 70(5):703–712

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kvasnicka T, Malikova I, Zenahlikova Z et al (2017) Rivaroxaban - metabolism, pharmacologic properties and drug interactions. Curr Drug Metab 18(7):636–642

    Article  PubMed  CAS  Google Scholar 

  • Laliberte F, Cloutier M, Nelson WW et al (2014) Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin 30(7):1317–1325

    Article  PubMed  CAS  Google Scholar 

  • Li XG, Wu YX, Sun SS et al (2015) Population pharmacokinetics of vancomycin in postoperative neurosurgical patients. J Pharm Sci 104(11):3960–3967

    Article  PubMed  CAS  Google Scholar 

  • Li XG, Wu YX, Sun SS et al (2016) Population pharmacokinetics of vancomycin in postoperative neurosurgical patients and the application in dosing recommendation. J Pharm Sci 105(11):3425–3431

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Wang XZ, Li DD et al (2022) Real-world comparisons of low-dose NOACs versus standard-dose NOACs or warfarin on efficacy and safety in patients with AF: a meta-analysis. Cardiol Res Pract 2022:4713826

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu XQ, Zhang YF, Ding HY et al (2022) Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation. Acta Pharmacol Sin 43(10):2723–2734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu XQ, Li ZR, Wang CY et al (2023) Is a lower dose of rivaroxaban required for Asians? A systematic review of a population pharmacokinetics and pharmacodynamics analysis of rivaroxaban. Pharmaceutics 15(2):588

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mueck W, Borris LC, Dahl OE et al (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100(3):453–461

    PubMed  CAS  Google Scholar 

  • Mueck W, Lensing AWA, Agnelli G et al (2011) 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 50(10):675–686

    Article  PubMed  CAS  Google Scholar 

  • Samama MM, Amiral J, Guinet C et al (2013) Monitoring plasma levels of factor Xa inhibitors: how, why and when? Expert Rev Hematol 6(2):155–164

    Article  PubMed  CAS  Google Scholar 

  • Singkham N, Phrommintikul A, Pacharasupa P et al (2022) Population pharmacokinetics and dose optimization based on renal function of rivaroxaban in Thai patients with non-valvular atrial fibrillation. Pharmaceutics 14(8):1744

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Suzuki S, Yamashita T, Kasai H et al (2018) 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 33(4):188–193

    Article  PubMed  CAS  Google Scholar 

  • Tanigawa T, Kaneko M, Hashizume K et al (2013) Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet 28(1):59–70

    Article  PubMed  CAS  Google Scholar 

  • Willmann S, Zhang LP, Frede M et al (2018) Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations. CPT-Pharmacometrics Syst Pharmacol 7(5):309–320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu XS, Moore K, Burton P et al (2012) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Brit J Clin Pharmacol 74(1):86–97

    Article  CAS  Google Scholar 

  • Yu HT, Yang PS, Jang E et al (2020) Label adherence of direct oral anticoagulants dosing and clinical outcomes in patients with atrial fibrillation. J Am Heart Assoc 9(12):e014177

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zdovc J, Petre M, Pislar M et al (2019) 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 75(6):817–824

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Chen WQ, Qin W et al (2023) Population pharmacokinetics and hemorrhagic risk analysis of rivaroxaban in elderly Chinese patients with nonvalvular atrial fibrillation. J Clin Pharmacol 63(1):66–76

    Article  PubMed  CAS  Google Scholar 

  • Zhang F, Chen X, Wu T et al (2022) Population pharmacokinetics of rivaroxaban in Chinese patients with non-valvular atrial fibrillation: a prospective multicenter study. Clin Pharmacokinet 61(6):881–893

    Article  PubMed  CAS  Google Scholar 

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Funding

This study was funded by research and application of clinical characteristic diagnosis and treatment technology in Beijing (grant no. Z221100007422032).

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Authors and Affiliations

  1. Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, Xicheng District, Beijing, 100050, China

    Ze Li, Siyu Yang, Zixin Hua & Xingang Li

  2. Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, No. 69 Yongding Road, Haidian District, Beijing, 100039, China

    Yanxia Lu

Authors
  1. Ze Li
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  2. Siyu Yang
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  3. Zixin Hua
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  4. Yanxia Lu
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  5. Xingang Li
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Contributions

Z.L. was responsible for the study design, data analysis, data interpretation, drafting and critical revision of the manuscript. S.Y., Z.H. were responsible for the provision of study materials or patients. Y.L., X.L. were responsible for the study concept and design, data interpretation, critical revision of the manuscript, approval of the final submission. All authors reviewed the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Yanxia Lu or Xingang Li.

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The authors declare no competing interests.

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This research was carried out at the Chinese PLA General Hospital with the official endorsement of the hospital’s institutional ethics committee.

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Li, Z., Yang, S., Hua, Z. et al. Population pharmacokinetics of rivaroxaban in Chinese deep vein thrombosis patients and the exposure simulation for dosing recommendation. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02798-7

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