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

PLoS One. 2014 Aug 22;9(8):e105891. doi: 10.1371/journal.pone.0105891. eCollection 2014.

Abstract

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / therapeutic use*
  • Asian People
  • Cytochrome P-450 CYP2C9 / genetics*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P450 Family 4
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Genetic
  • Treatment Outcome
  • Vitamin K Epoxide Reductases / genetics*
  • Warfarin / blood
  • Warfarin / pharmacokinetics*
  • Warfarin / therapeutic use*

Substances

  • Anticoagulants
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases

Associated data

  • ClinicalTrials.gov/NCT02065388

Grants and funding

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI C, 20590548) and the Department of Health, Taiwan (DOH101-TD-PB-111-TM005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.