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

Author

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, and Yuan-Tsong Chen

Subjects
Medicine, Science
Abstract

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

Published
2014
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2. Factors influencing pharmacokinetics of warfarin in African-Americans: implications for pharmacogenetic dosing algorithms

Author

Minoli A. Perera, Wenndy Hernandez, Larisa H. Cavallari, Naoko Kaneko, Katarzyna Drozda, Rui Nagai, Shitalben R. Patel, Harumi Takahashi, Manabu Hibiya, Edith A. Nutescu, and Minami Ohara

Subjects
Adult, Male, Genotype, Body Surface Area, Metabolic Clearance Rate, Population, Pharmacology, Loading dose, Models, Biological, Polymorphism, Single Nucleotide, Article, Pharmacokinetics, Vitamin K Epoxide Reductases, Genetics, Medicine, Humans, Dosing, International Normalized Ratio, education, CYP2C9, Aged, Cytochrome P-450 CYP2C9, Body surface area, Aged, 80 and over, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Maintenance dose, Body Weight, Warfarin, Anticoagulants, Middle Aged, Black or African American, Molecular Medicine, Female, business, Algorithm, Algorithms, medicine.drug
Abstract

Aim: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African–Americans. Methods: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African–Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African–Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. Results: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m2/-10 kg reduction in CL[S], respectively) in African–Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. Conclusion: African–Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014

Published
2015

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