Details

Autor(en) / Beteiligte

• Ohara, Minami
• Suzuki, Yasuhiko
• Shinohara, Saki
• Gong, Inna Y.
• Schmerk, Crystal L.
• Tirona, Rommel G.
• Schwarz, Ute I.
• Wen, Ming-Shien
• Lee, Ming Ta Michael
• Mihara, Kiyoshi
• Nutescu, Edith A.
• Perera, Minoli A.
• Cavallari, Larisa H.
• Kim, Richard B.
• Takahashi, Harumi

Titel

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations

Ist Teil von

• Clinical pharmacokinetics, 2019-08, Vol.58 (8), p.1077-1089

Ort / Verlag

Cham: Springer International Publishing

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Background Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. Methods Using population PK/PD analysis, we attempted to identify predictors of S -warfarin clearance [CL(S)] and half maximal effective concentration (EC 50 ) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. Results Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p  < 0.01). EC 50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 μg/mL for Asian, White and African American patients, respectively, p  < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic ( CYP2C9*3,*8 and VKORC1 −1639G>A ) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC 50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. Conclusions Although there were contrasting racial differences in CL(S) and EC 50 that impacted on the INR, the racial difference in EC 50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.