Clinical Pharmacokinetics

, Volume 51, Issue 12, pp 799–808 | Cite as

Inter-Individual Differences in Baseline Coagulation Activities and Their Implications for International Normalized Ratio Control During Warfarin Initiation Therapy

  • Yosuke Ichimura
  • Harumi TakahashiEmail author
  • Michael T. M. Lee
  • Mari Shiomi
  • Kiyoshi Mihara
  • Takashi Morita
  • Yuan-Tsong Chen
  • Hirotoshi Echizen
Original Research Article


Background and Objective

Genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) and patient demographic characteristics are responsible for inter-individual differences in warfarin maintenance dosage requirements. At present, however, the factors associated with over-anticoagulation responses, especially before achieving the maintenance phase, have not been completely clarified. In this study, we investigated the effects of baseline coagulation activity assessed in terms of the level of fully carboxylated plasma normal prothrombin (NPT) on international normalized ratio (INR) control during the induction phase of warfarin therapy. Our objectives were to (1) identify factors associated with inter-patient variability in baseline NPT (NPT0); (2) estimate the therapeutic NPT (NPTtx) levels that can achieve an INR of 2–3; and (3) investigate the influence of NPT0 on the INR response to warfarin by employing modelling and simulation techniques.


We measured NPT before (NPT0) and during the introduction of warfarin therapy for up to 3 months and analysed functional single nucleotide polymorphisms (SNPs) of VKORC1 and CYP4F2 in 179 Chinese patients. The patients were classified into tertile groups according to NPT0 values (i.e. high, intermediate and low groups), and in each group the NPTtx achieving therapeutic INR, the absolute reduction of NPT from NPT0 to NPTtx, and the percentage inhibition of NPT0 [{(NPT0 − NPTtx)/NPT0} × 100] were obtained. The nonlinear relationship between NPT and INR was modelled on the basis of the INR value before warfarin treatment (INR0) added by the nonlinear increase in INR after warfarin initiation, which was predicted using the percentage inhibition of NPT0 and a nonlinear coefficient (λ). The population parameter λ and its inter-individual variability and intra-individual variability in INR in the NPT–INR model were estimated by nonlinear mixed-effect modelling software NONMEM®.


Multivariate analysis identified age and liver disease as covariates of NPT0, but none of the SNPs had a significant influence. Although the mean absolute NPT reduction necessary to achieve NPTtx was dependent on NPT0 (i.e. the higher the NPT0, the larger the reduction in NPT), the percentage inhibition was within the narrow range of 67–72 % of NPT0, irrespective of NPT0. However, a significantly higher percentage inhibition (80 % on average) was observed in patients with INR values exceeding 4.0. As the nonlinear coefficient λ in the developed model was dependent on NPT0 (i.e. the higher the NPT0, the larger the nonlinear λ value), the simulated nonlinear NPT–INR curves were superimposable in the three respective NPT0 groups, and the only difference was the starting median NPT0 level. As a result, a steeper increase in the slope of the nonlinear NPT–INR curve might be expected in patients with a lower NPT0 after initiation of warfarin.


The present study suggests that INR may be prolonged by warfarin nonlinearly as a function of the percentage inhibition of NPT0. Furthermore, these results indicate that NPT0 may contribute to inter-individual variability in the INR response, and that patients with low NPT0 may have the potential to show a sharp increase in INR during initiation therapy with warfarin.


Warfarin International Normalize Ratio Warfarin Dose Therapeutic International Normalize Ratio International Normalize Ratio Control 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI C, 20590548 and ORC160’11) and the National Research Program for Genomic Medicine, National Science Council, Taiwan. The authors declare no conflicts of interest. The authors wish to thank Naoko Kaneko for her excellent technical assistance.


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Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • Yosuke Ichimura
    • 1
  • Harumi Takahashi
    • 2
    Email author
  • Michael T. M. Lee
    • 3
  • Mari Shiomi
    • 2
  • Kiyoshi Mihara
    • 4
  • Takashi Morita
    • 5
  • Yuan-Tsong Chen
    • 3
  • Hirotoshi Echizen
    • 1
  1. 1.Department of PharmacotherapyMeiji Pharmaceutical UniversityTokyoJapan
  2. 2.Department of BiopharmaceuticsMeiji Pharmaceutical UniversityKiyoseJapan
  3. 3.Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
  4. 4.Faculty of Pharmacy, Center for Clinical PharmacyMusashino UniversityTokyoJapan
  5. 5.School of MedicineJuntendo UniversityTokyoJapan

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