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- Title
Determinants of the Over-Anticoagulation Response during Warfarin Initiation Therapy in Asian Patients Based on Population Pharmacokinetic-Pharmacodynamic Analyses.
- Authors
Ohara, Minami; Takahashi, Harumi; Lee, Ming Ta Michael; Wen, Ming-Shien; Lee, Tsong-Hai; Chuang, Hui-Ping; Luo, Chen-Hui; Arima, Aki; Onozuka, Akiko; Nagai, Rui; Shiomi, Mari; Mihara, Kiyoshi; Morita, Takashi; Chen, Yuan-Tsong
- 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
- Subjects
WARFARIN; BLOOD coagulation; PHARMACOKINETICS; PHARMACODYNAMICS; ASIANS; GENETIC polymorphisms; DISEASES
- Publication
PLoS ONE, 2014, Vol 9, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0105891