The AAPS Journal

, 21:80 | Cite as

Population Pharmacokinetics and Pharmacodynamics of Apixaban Linking Its Plasma Concentration to Intrinsic Activated Coagulation Factor X Activity in Japanese Patients with Atrial Fibrillation

  • Satoshi Ueshima
  • Daiki Hira
  • Chiho Tomitsuka
  • Miki Nomura
  • Yuuma Kimura
  • Takuya Yamane
  • Yohei Tabuchi
  • Tomoya Ozawa
  • Hideki Itoh
  • Minoru Horie
  • Tomohiro Terada
  • Toshiya KatsuraEmail author
Research Article


Apixaban is used in the prevention and treatment of patients with deep vein thrombosis or pulmonary embolism, and in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In this study, we aimed to elucidate intrinsic factors affecting efficacy of apixaban by conducting population pharmacokinetic and pharmacodynamic analysis using data from 81 Japanese AF patients. The intrinsic FXa activity was determined to assess the pharmacodynamic effect of apixaban. The pharmacokinetic and pharmacodynamic profiles were described based on a one-compartment model with first-order absorption and a maximum inhibitory model, respectively. Pharmacokinetic and pharmacodynamic analysis was conducted using a nonlinear mixed effect modeling program. The population pharmacokinetic parameters of apixaban were fixed at the reported values in our recent study. The population mean of half-maximal inhibitory concentration (IC50) of apixaban was estimated to be 45.3 ng/mL. The population mean IC50 decreased 27.7% for patients with heart failure, but increased 55% for patients with a medical history of cerebral infarction. In contrast, no covariates affected the population mean of baseline of intrinsic FXa activity (BASE) and maximum effect (Imax) value of apixaban. The population mean of BASE and Imax value were estimated to be 40.2 and 38.4 nmol/min/mg protein, respectively. The present study demonstrates for the first time that the co-morbidity of heart failure as well as the medical history of cerebral infarction are an intrinsic factor affecting the pharmacodynamics of apixaban.


apixaban cerebral infarction heart failure population pharmacokinetics and pharmacodynamics 


Funding Information

This study was supported in part by JSPS KAKENHI Grant Number 15K18938, the Japan Research Foundation for Clinical Pharmacology, and the Uehara Memorial Foundation.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12248_2019_353_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 26 kb)
12248_2019_353_MOESM2_ESM.docx (15 kb)
ESM 2 (DOCX 15 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Satoshi Ueshima
    • 1
  • Daiki Hira
    • 1
    • 2
  • Chiho Tomitsuka
    • 1
  • Miki Nomura
    • 1
  • Yuuma Kimura
    • 1
  • Takuya Yamane
    • 1
  • Yohei Tabuchi
    • 2
  • Tomoya Ozawa
    • 3
  • Hideki Itoh
    • 3
  • Minoru Horie
    • 3
    • 4
  • Tomohiro Terada
    • 2
  • Toshiya Katsura
    • 1
    Email author
  1. 1.College of Pharmaceutical SciencesRitsumeikan UniversityKusatsuJapan
  2. 2.Department of PharmacyShiga University of Medical Science HospitalOtsuJapan
  3. 3.Department of Cardiovascular MedicineShiga University of Medical ScienceOtsuJapan
  4. 4.Center for Epidemiologic Research in AsiaShiga University of Medical ScienceOtsuJapan

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