PLoS ONE (Jan 2014)

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

  • Minami Ohara,
  • Harumi Takahashi,
  • Ming Ta Michael Lee,
  • Ming-Shien Wen,
  • Tsong-Hai Lee,
  • Hui-Ping Chuang,
  • Chen-Hui Luo,
  • Aki Arima,
  • Akiko Onozuka,
  • Rui Nagai,
  • Mari Shiomi,
  • Kiyoshi Mihara,
  • Takashi Morita,
  • Yuan-Tsong Chen

DOI
https://doi.org/10.1371/journal.pone.0105891
Journal volume & issue
Vol. 9, no. 8
p. e105891

Abstract

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UNLABELLED:To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. TRIAL REGISTRATION:ClinicalTrials.gov NCT02065388.