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Pharmacogenomics 2019 Apr 15. Epub 2019 Apr 15.

Molecular Immunopathology & Histocompatibility Unit, Onassis Cardiac Surgery Center, Athens, Greece.

Vitamin-K antagonists (VKAs) have remained the mainstay of oral anticoagulant therapy for the treatment and prevention of thromboembolism. The management of treatment with VKAs is challenging due to their narrow therapeutic index and the wide interindividual variation in response to therapy. Variants of the CYP2C9 and the VKORC1 gene account for 30-50% of the variability in dosing requirements, and it has been proposed that genotyping of these loci could facilitate management of VKA therapy and minimize risk of overanticoagulation, even in very low doses. Read More

Br J Clin Pharmacol 2019 Apr 1. Epub 2019 Apr 1.

Coagulation Disorders Unit, Clinical Chemistry, University of Helsinki and HUSLAB, Helsinki University Hospital, POB 720, 00029, Helsinki, Finland.

Aims: Warfarin dose requirement varies significantly. We compared the clinically established international normalized ratio (INR) -based doses among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms.

Methods: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c. Read More

OMICS 2019 Mar;23(3):152-166

1 Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Coumarins such as warfarin are prescribed for prevention and treatment of thromboembolic disorders. Warfarin remains the most widely prescribed and an anticoagulant of choice in Africa. Warfarin use is, however, limited by interindividual variability in pharmacokinetics and a narrow therapeutic index. Read More

Clin Pharmacokinet 2019 Feb 28. Epub 2019 Feb 28.

Department of Biopharmaceutics, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose, Tokyo, 204-8588, Japan.

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) 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. Read More

Mol Biol Rep 2019 Apr 2;46(2):1825-1833. Epub 2019 Feb 2.

Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

It was aimed to underline the importance and explain the meaning of genetic testing in warfarin dosing and investigate and evaluate the contributions of the CYP2C9, VKORC1, and CYP4F2 variants in a Turkish population. Two hundred patients were genotyped for CYP2C9 (rs1799853, rs1057910 and rs56165452), VKORC1 (rs9934438, rs8050894, rs9923231, rs7294 and rs2359612) and CYP4F2 (rs2108622), yet, only 127 patients were found suitable for further evaluation in terms of their personal response to warfarin due to long term usage and available INR and dose usage information. The DNA sequences were determined by the ABI PRISM 3100 Genetic Analyzer to 3130xl System (Applied Biosystems, Foster City, California). Read More

Basic Clin Pharmacol Toxicol 2018 Dec 27. Epub 2018 Dec 27.

Research Division, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.

We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Read More

OMICS 2019 01 19;23(1):36-44. Epub 2018 Dec 19.

1 Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .

Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index. The rs12777823G>A single-nucleotide polymorphism (SNP) in the CYP2C gene cluster has been shown to influence optimal warfarin doses in African Americans. We report here effects of rs12777823G>A SNP on warfarin dose requirements in two South African population groups, black Africans (BA) and mixed ancestry (MA). Read More

J Physiol Pharmacol 2018 Aug 10;69(4). Epub 2018 Nov 10.

Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

Predicting the clinical consequences of anticoagulant therapy by identifying gene variants could help in the risk assessment of thrombosis or bleeding before and after surgery and may result in choosing more beneficial therapy. This work provides an overview of pharmacogenetic data of commonly used anticoagulant medication. The review focuses on polymorphisms influencing the efficacy and safety of the parenteral and oral anticoagulants. Read More

Pharmgenomics Pers Med 2018 16;11:169-178. Epub 2018 Oct 16.

GENIUROS Research Group, Center For Research in Genetics and Genomics - CIGGUR, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia,

Purpose: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter- and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. and gene polymorphisms affect warfarin metabolism and dosage. Read More

Pharmacogenomics 2018 Nov 22;19(17):1357-1371. Epub 2018 Oct 22.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, AL 35294, USA.

Despite the introduction of direct acting oral anticoagulants, warfarin remains the most commonly prescribed oral anticoagulant. However, warfarin therapy is plagued by the large inter- and intrapatient variability. The variability in dosing fueled research to identify clinical and genetic predictors and develop more accurate dosing algorithms. Read More

PLoS One 2018 19;13(10):e0205872. Epub 2018 Oct 19.

Easton Cardiovascular Associates, Easton, PA, United States of America.

Warfarin dosing remains challenging due to narrow therapeutic index and highly individual variability. Incorrect warfarin dosing is associated with devastating adverse events. Remarkable efforts have been made to develop the machine learning based warfarin dosing algorithms incorporating clinical factors and genetic variants such as polymorphisms in CYP2C9 and VKORC1. Read More

Thromb Res 2018 11 1;171:167-170. Epub 2018 Oct 1.

Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, NE1 7RU, UK. Electronic address:

Introduction: Warfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal. Read More

Ann Thorac Surg 2018 Dec 8;106(6):1774-1781. Epub 2018 Sep 8.

Division of Cardiac Surgery, Key Laboratory on Assisted Circulation, Ministry of Health, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address:

Background: The clinical utility of genotype-guided warfarin dosing remains controversial. The objective of this trial was to evaluate the efficacy and safety of genotype-guided warfarin dosing in East Asians.

Methods: A double-blind, randomized control trial was performed to compare a genotype-guided dosing algorithm (CYP2C9, VKORC1, and CYP4F2) with a clinical-guided one in the initiation treatment for patients with mechanical heart valves. Read More

JACC Basic Transl Sci 2018 Aug 28;3(4):545-549. Epub 2018 Aug 28.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.

The U.S. Food and Drug Administration recently marked 10 years since first updating the labeling for warfarin (often referred to as the "poster child" of pharmacogenomics) to include information regarding the potential impact of and genetic variation on warfarin dosing requirements and risks. Read More

Pediatr Cardiol 2019 Jan 18;40(1):29-37. Epub 2018 Aug 18.

Department of Cardiology, Children's Hospital of Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders, 136# Zhongshan 2nd Rd. Yuzhong District, Chongqing, 400014, China.

Long-term oral warfarin is recommended in pediatric Kawasaki disease patients with large coronary artery aneurysms; however, heterogeneity is considerable. This study aimed to determine variables affecting warfarin dosage in Kawasaki disease. The enrolled individuals (194 children) were divided into four groups: (1) Cases with severe coronary artery lesions (CAL) of IV to V degrees or thrombogenesis treated with oral warfarin were assigned to Group A; (2) Group B, CAL of I degrees; (3) Group C, CAL of II and III degrees cases with small or medium-sized CAL not treated with warfarin; (4) Group D, normal children without Kawasaki disease. Read More

BMC Med 2018 07 10;16(1):104. Epub 2018 Jul 10.

Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.

Background: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved.

Methods: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. Read More

J Thromb Haemost 2018 Sep 17;16(9):1732-1742. Epub 2018 Jul 17.

Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45. Read More

Blood Coagul Fibrinolysis 2018 Sep;29(6):496-500

Clinical Pharmacology Section, Internal Medicine Department.

: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Read More

Thromb Res 2018 07 8;167:32-36. Epub 2018 May 8.

Pediatric Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. Electronic address:

Introduction: Warfarin therapy is recommended in children with giant coronary artery aneurysms (GCAAs) after Kawasaki disease (KD). Large individual variability makes it difficult to predict the warfarin dose. Polymorphisms in the vitamin K expoxide reductase 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) genes have been reported to influence the warfarin dose. Read More

Br J Clin Pharmacol 2018 Sep 21;84(9):1868-1882. Epub 2018 Jun 21.

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China.

Aims: Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. Read More

Indian J Hematol Blood Transfus 2018 Apr 27;34(2):328-336. Epub 2016 Sep 27.

3Biochemistry Department, Pharos University in Alexandria, Alexandria, Egypt.

Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Read More

Ther Drug Monit 2018 06;40(3):362-368

Department for Pharmacogenomics and Therapy Individualization, University Hospital Center Zagreb, Zagreb, Croatia.

Background: Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy. Read More

Cardiovasc Ther 2018 Apr 3;36(2). Epub 2018 Jan 3.

Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.

Aim: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin dosing algorithms derived from Caucasian, Asian, and mixed population to identify a suitable algorithm for Thai population.

Methods: Ten warfarin dosing algorithms derived from different population including Caucasian, East Asian, South-East Asian, and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP). Read More

Lab Med 2017 Dec;49(1):25-34

Department of Cardiac Surgery, Madani Heart Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study. Read More

Turk J Med Sci 2017 08 23;47(4):1239-1246. Epub 2017 Aug 23.

Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. Read More

JAMA 2017 09;318(12):1115-1124

Washington University in St Louis, St Louis, Missouri.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.

Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Read More

Front Pharmacol 2017 7;8:347. Epub 2017 Jun 7.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto RicoSan Juan, PR, United States.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Read More

J Thromb Haemost 2017 08 17;15(8):1708. Epub 2017 Jul 17.

Department of Thrombosis and Haemostasis, National Institute of Immunohaematology (ICMR), Mumbai, India.

Eur J Pharm Sci 2017 Nov 11;109S:S9-S14. Epub 2017 May 11.

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida at Lake Nona, Orlando, FL, USA. Electronic address:

Current genotype-guided algorithms for warfarin dosing fail to deliver optimal performance in two aspects: 1) these algorithms are not able to achieve the same level of benefits in non-white populations, since they were developed based on multivariate regression analysis with mostly European/White data and did not include genetic variants found frequently in non-white populations; 2) these algorithms do not account for the dynamic dose/response relationship and were limited in their usefulness to guide dosing during the initiation phase, as the possession of variant VKORC1 and/or CYP2C9 polymorphisms has been associated with a more rapid attainment of target international normalized ratio (INR) and higher risk of over-anticoagulation even in genotype-guided patients. To address these shortcomings, we report on the novel use of a previously published kinetic/pharmacodynamic (K/PD) model to develop a warfarin dosing nomogram to be used across genotypes and ethnicities. Our approach leverages data from both ethnically diverse and European patients, while accounting for the differential dose/response behaviors due to VKORC1 and CYP2C9 genotypes. Read More

Clin Pharmacol Drug Dev 2018 03 3;7(3):256-262. Epub 2017 Apr 3.

Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China, 250012.

This study was designed to investigate the pharmacokinetics of an innovative film-coated warfarin sodium tablet and to compare it with the marketed sugar-coated warfarin sodium tablet in humans. A single-dose, open-label, randomized, two-way crossover study was performed in 24 healthy Chinese male volunteers. They were administered 2. Read More

Clin Pharmacol Ther 2017 Sep 4;102(3):397-404. Epub 2017 Apr 4.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. Read More

J Thromb Haemost 2017 04 25;15(4):735-743. Epub 2017 Mar 25.

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Read More

Pharmacogenomics 2017 Feb 23;18(3):245-253. Epub 2017 Jan 23.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Aim: This study aimed to determine clinical utility of genotype-guided dosing for warfarin in Han-Chinese.

Methods: A total of 320 patients were randomly assigned International Warfarin Pharmacogenetic Consortium algorithm, Taiwan algorithm and optimal clinical care arms. The primary outcome of the study was the percentage of time in the therapeutic range during the first 90 days of treatment. Read More

Australas Phys Eng Sci Med 2017 Mar 12;40(1):249-258. Epub 2017 Jan 12.

Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Rd. 2, Guangzhou, Guangdong, 510080, People's Republic of China.

The optimal dose of warfarin depends on polymorphisms in the VKORC1 (the vitamin K epoxide reductase complex subunit (1) and CYP2C9 (cytochrome P450 2C9) genes. To minimize the risk of adverse reactions, warfarin dosages should be adjusted according to results from rapid and simple monitoring methods. However, there are few pharmacogenetic-guided warfarin dosing algorithms that are based on large cohorts from the Chinese population, especially patients with atrial fibrillation. Read More

Medicine (Baltimore) 2017 Jan;96(2):e5658

aDepartment of Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing bDepartment of Pediatrics, Peking University First Hospital, Beijing cDepartment of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Disease dExperimental Center, Beijing Institute of Heart, Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Read More

Clin Appl Thromb Hemost 2018 Mar 4;24(2):353-359. Epub 2017 Jan 4.

1 National Institute of Immunohaematology (ICMR), Department of Thrombosis and Haemostasis, KEM Hospital, Parel, Mumbai, India.

The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c. Read More

Clin Pharmacol Ther 2017 May 29;101(5):675-683. Epub 2016 Dec 29.

Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7. Read More

PLoS One 2016 19;11(12):e0168732. Epub 2016 Dec 19.

College of Pharmacy, Qatar University, Doha, Qatar.

Background: Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. Read More

Analyst 2017 01;142(2):366-374

Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA. and Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA and Department of Mechanical Engineering, University of Virginia, Charlottesville, Virginia 22904, USA.

Warfarin, a commonly prescribed oral anticoagulant, is burdened by a narrow therapeutic index and high inter-individual variability in response, making it the second leading cause of drug-related emergency room visits. Since genetic factors contribute significantly to warfarin sensitivity, a genotype-guided dosing strategy may reduce the occurrence of adverse events. While numerous methods have been demonstrated for warfarin genotyping, the specifications of most assays with respect to turnaround time and cost are not ideal for routine testing. Read More

Pac Symp Biocomput 2017 ;22:545-556

Div. of Biomedical Informatics and Personalized Med., University of Colorado, 13001 E. 17th Pl. MS F-563 Aurora, CO 80045, USA,

The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. Read More

Clin Ther 2016 Dec 23;38(12):2666-2674.e1. Epub 2016 Nov 23.

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Republic of Korea. Electronic address:

Purpose: The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients.

Methods: The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy.

Findings: A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk). Read More

Clin Appl Thromb Hemost 2018 Mar 22;24(2):323-329. Epub 2016 Nov 22.

3 Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.

Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. Read More

Ther Drug Monit 2016 12;38(6):677-683

*School of Pharmacy, University of Otago, Dunedin, New Zealand;†Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Malaysia;‡Department of Surgical Sciences, University of Otago, Dunedin, New Zealand;§Department of Haematology, Glasgow Royal Infirmary, Glasgow, Scotland;¶Department of Pharmacy, Glasgow Royal Infirmary, Glasgow, Scotland; and‖Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland.

Background: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions.

Methods: The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. Read More

PLoS One 2016 16;11(9):e0162866. Epub 2016 Sep 16.

Erasmus University Medical Center, Faculty of Medicine, Department of Bioinformatics, Rotterdam, the Netherlands.

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Read More

Pharmacogenomics J 2017 12 9;17(6):494-500. Epub 2016 Aug 9.

Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.

Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h, P<0.01). Read More

Clin Pharmacol Ther 2016 Nov 18;100(5):427-430. Epub 2016 Aug 18.

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Implementation of pharmacogenetic-guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non-white populations. However, current evidence indicates that algorithm-guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm-guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point-of-care dose recommendations. Read More

Syst Rev 2016 06 23;5(1):105. Epub 2016 Jun 23.

Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada.

Background: Despite its shortcomings, warfarin is still the most commonly prescribed anticoagulant to prevent thromboembolism in children. In adults, numerous studies confirmed the robust relationship between warfarin maintenance doses and single nucleotide polymorphisms of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase (VKORC1), and cytochrome P450 4F2 (CYP4F2). However, their effect in children still remains to be determined. Read More

Indian J Pharmacol 2016 May-Jun;48(3):258-63

Department of Pharmacy, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.

Objective: This study aims to screen and validate five individual warfarin dosing models (four Asian model algorithms, namely, Ohno, Wen, Miao, Huang, and the algorithm of International Warfarin Pharmacogenetic Consortium, namely IWPC algorithm) with the aim of evaluating their accuracy, practicality, and safety.

Materials And Methods: Patients' CYP2C9*3 and VKORC1-1639G >A genes were genotyped, and patient-related information and steady warfarin doses were recorded. The difference between the predicted dose and actual maintenance dose of each model was compared. Read More

Pharmacogenomics J 2016 Oct 7;16(5):478-84. Epub 2016 Jun 7.

Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0. Read More