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Thrombosis & Anticoagulation Research Group Group

Thrombosis & Anticoagulation Research Group Group. Influence of age and CYP2C9 polymorphism on warfarin dose requirements Farhad Kamali Wolfson Unit of Clinical Pharmacology University of Newcastle. Wolfson Unit of Clinical Pharmacology, University of Newcastle. Background to warfarin.

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Thrombosis & Anticoagulation Research Group Group

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  1. Thrombosis & Anticoagulation Research Group Group Influence of age and CYP2C9 polymorphism on warfarin dose requirementsFarhad KamaliWolfson Unit of Clinical PharmacologyUniversity of Newcastle

  2. Wolfson Unit of Clinical Pharmacology, University of Newcastle Background to warfarin Warfarin as rat poison (1948) Unsuccessful suicide attempt (1951) Clinical use of warfarin in 1954

  3. Thrombosis & Anticoagulation Research Group Group Atrial fibrillation increases risk of stroke five-fold Warfarin therapy decreases risk of stroke by 68%

  4. Thrombosis & Anticoagulation Research Group Group Limitations of warfarin  Onset/Offset -delayed  Unpredictable response -require monitoring  Narrow therapeutic index -require monitoring  Factors influence response -require monitoring  Monitoring assay -problematic  Side effects -bleeding  Reversibility -slow  Frequent dose changes -require management

  5. Thrombosis & Anticoagulation Research Group Group Inter-individual differences in warfarin dose requirements • >120-fold difference in dosage requirement  Increased risk of bleeding at the initiation stage of warfarin therapy

  6. Thrombosis & Anticoagulation Research Group Group Factors contributing to inter-individual variability: • Disease • Drug interactions • Age 21% fall in warfarin dosage over 15 years Wynne et al. Age & Ageing (1996) 25: 429-431 -ve correlation between age and liver volume +ve correlation between liver volume and dose Wynne, et al. Br. J. Clin. Pharmacol. (1995) 40: 203-207 • Genetics

  7. ONa C6H5 CHCH2COH2 O O Thrombosis & Anticoagulation Research Group Group Warfarin [(R)- & (S)-enantiomers)] CYP2C9*1 CYP2C9*2 (12% activity) CYP2C9*3 (5% activity) Furuya, et al. Pharmacogenetics (1995) 5: 389-392 Steward, et al. Pharmacogenetics (1997) 7: 361-367

  8. Case 1 10 8 6 INR 4 2 0 Thrombosis & Anticoagulation Research Group Group 0 1 2 3 4 5 6 7 8 9 10 11 12 Warfarin (10 mg) Vit K (2 mg) Vit K (2 mg) Case 2 15 10 INR 5 0 0 2 4 5 7 8 11 12 13 Warfarin (10 mg) Warfarin (5 mg) Vit K (0.5 mg) Vit K (1 mg) Khan et al. Age & Ageing.In press Day

  9. Thrombosis & Anticoagulation Research Group Group Influence of age, body size and CYP2C9 polymorphism on warfarin dose requirements 178 patients (95 males) on warfarin with stable control (target INR 2.0-3.0) Age range: 24-90 years; median 72 Blood sample taken on arrival to clinic

  10. Thrombosis & Anticoagulation Research Group Group Laboratory measurements: Venous INR Genotyping for CYP2C9*1, CYP2C9*2 and CYP2C9*3 Plasma warfarin enantiomer concentrations

  11. Thrombosis & Anticoagulation Research Group Group Median (range) age and (meansd; range; median) warfarin daily dose requirement for the three groups of patients with different CYP2C9 genotypes *1/ *1 (n = 104)*1/ *2 (n = 44)*1/*3 (n = 23) Age (years)72 (24-90)73 (36-88)75 (44-90) Warfarin daily dose (mg)4.101.80 (1.0-10.6; 3.9) 3.251.71 (0.8-8.5; 3.0)2.851.44 (0.5-6.0; 2.9) 5 patients (aged 62-80 y) with *2/*2 genotype (daily dose: 1.22 mg (0.8-2.2) one patient (62 y) with *2/*3 (dd: 1 mg) and one (77 y) with *3/*3 genotype (dd: 0.75 mg).

  12. Thrombosis & Anticoagulation Research Group Group Correlations with dose Correlation coefficient (r)p-value Age-0.35<0.0001 CLSW0.52<0.0001 CLRW0.36<0.0001 CLtotal0.53<0.0001 BSA0.210.022 INR0.040.6

  13. Thrombosis & Anticoagulation Research Group Group Regression equation for modelling warfarin daily dose requirements based on age and genotype Model x-variables Regression equation P value Model 3 (age and genotype *1)Dose = 7.55 – 0.05 x age 0.001/.000 Model 3 (age and genotype *2)Dose = 6.83 – 0.05 x age .000/0.013 Model 3 (age and genotype *3)Dose = 6.55 – 0.05 x age .000/009 (y-variable is dose (D) in all the above three models).

  14. Thrombosis & Anticoagulation Research Group Group Age(years)CYP2C9*1CYP2C9*2CYP2C9*3 Estimated warfarin daily dose (mg) (95% prediction interval) based on patient age and genotype 6.5 (2.9, 10.2) 6.3 (2.7, 9.9) 6.0 (2.5, 9.6) 5.8 (2.2, 9.3) 5.5 (2.0, 9.0) 5.3 (1.8, 8.8) 5.0 (16, 8.5) 4.8 (1.3, 8.2) 4.5 (1.1, 7.9) 4.3 (0.9, 7.7) 4.0 (0.6, 7.4) 3.8 (0.4, 7.2) 3.5 (0.9, 6.9) 3.3 (-0.2, 6.7) 3.0 (-0.5, 6.5) 5.8 (1.9, 9.8) 5.6 (1.8, 9.4) 5.3 (1.6, 9.0) 5.1 (1.5, 8.7) 4.8 (1.3, 8.3) 4.6 (1.1, 8.0) 4.3 (1.0, 7.7) 4.1 (0.8, 7.4) 3.8 (0.5, 7.1) 3.5 (0.3, 6.8) 3.3 (0.1, 6.5) 3.0 (-0.2, 6.3) 2.8 (-0.5, 6.0) 2.5 (-0.8, 5.8) 2.3 (-1.1, 5.6) 5.5 (1.3, 9.8) 5.3 (1.2, 9.4) 5.0 (1.1, 9.0) 4.8 (1.0, 8.6) 4.5 (0.8, 8.3) 4.3 (0.7, 7.9) 4.0 (0.5, 7.5) 3.8 (0.3, 7.2) 3.5 (0.1, 6.9) 3.3 (-0.1, 6.6) 3.0 (-0.3, 6.4) 2.8 (-0.6, 6.1) 2.5 (-0.8, 5.9) 2.3 (-1.1, 5.7) 2.0 (-1.5, 5.5) 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

  15. Thrombosis & Anticoagulation Research Group Group Conclusions Age and genetic polymorphism contribute to inter-individual variability in warfarin response and should be allowed for in the induction phase Modification of computer softwares for warfarin dosing.

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