Benjamin D. HornePetra A. LenziniMia WadeliusAndrea L. JorgensenStephen E. KimmelPaul M. RidkerNiclas ErikssonJeffrey L. AndersonMunir PirmohamedNita A. LimdiRobert C. PendletonGwendolyn A. McmillinJames K. BurmesterDaniel KurnikC. Michael SteinMichael D. CaldwellCharles S. EbyAnders RaneJonatan D. LindhJae Gook ShinHo Sook KimPantep AngchaisuksiriRobert J. GlynnKathryn E. KronquistJohn F. CarlquistGloria R. GriceRobert L. BarrackJuan LiBrian F. GageIntermountain Medical CenterUniversity of UtahWashington University in St. LouisUppsala UniversitetUniversity of LiverpoolUniversity of PennsylvaniaHarvard Medical SchoolBrigham and Women's HospitalAkademiska SjukhusetUniversity of AlabamaARUP LaboratoriesMarshfield ClinicVanderbilt UniversityKarolinska InstitutetInje University, College of MedicineMahidol UniversityKaiser PermanenteSt. Louis College of Pharmacy2018-06-112018-06-112012-02-10Thrombosis and Haemostasis. Vol.107, No.2 (2012), 232-240034062452-s2.0-84863012482https://repository.li.mahidol.ac.th/handle/20.500.14594/14952By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index. Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R 2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R 2 = 69.1% (p < 0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy. © Schattauer 2012.Mahidol UniversityMedicineArticleSCOPUS10.1160/TH11-06-0388