Optimal dosing of warfarin in a pediatric cohort: height, INR target, VKORC1 and CYP2C9 genotypes are the main contributors of the dose requirement

Transcription

1 Optimal dosing of warfarin in a pediatric cohort: height, INR target, VKORC1 and CYP2C9 genotypes are the main contributors of the dose requirement Caroline Moreau et Fanny Bajolle JESFC 2012, Paris

2 Introduction WARFARIN Pharmacological target Vitamin K epoxide reductase complex subunit 1 (VKORC1) Inhibition of Vitamin K cycle Metabolism Cytochrome P450 2C9 (CYP2C9) Inactive metabolites Elimination Wide interindividual variability in warfarin response

3 Interindividual variability in coumarinic derivatives sensitivity Non genetic factors Age, sex, BMI Genetic factors VKA pharmacological target VKORC1 Dietary VKA response Comorbidities Medications VKA metabolism CYP2C9 Vitamin K metabolism CYP4F2 *Pharmacogenetics: influence of DNA sequence variations on drug response

4 Auto-mesure de l INR en pédiatrie Aim of the study To determine the relative contribution of pharmacogenetic (VKORC1, CYP2C9, CYP4F2) and non genetic factors on VKA response in children warfarin and fluindione dose requirement Time spent within, above and below the INR range (data not shown)

5 Inclusion criteriae: educational program age, birth to 18 years Study design VKA therapy for at least the past 2 months stable anticoagulation (INR measured within the therapeutic range for 3 consecutive INR determinations at 2-weeks intervals) written informed consent obtained from legal guardians

6 Inclusion criteriae: educational program age, birth to 18 years VKA therapy for at least the past 2 months stable anticoagulation (INR measured within the therapeutic range for 3 consecutive INR determinations at 2-weeks intervals) written informed consent obtained from legal guardians Collected data: Study design demographic: age, gender, height, weight, body surface area clinical: indication for VKA therapy therapeutic: associated medications, weekly VKA maintenance dose biological: INR values during the follow-up genetic: VKORC1, CYP2C9, CYP4F2 polymorphisms

7 Inclusion criteriae: educational program age, birth to 18 years VKA therapy for at least the past 2 months stable anticoagulation (INR measured within the therapeutic range for 3 consecutive INR determinations at 2-weeks intervals) written informed consent obtained from legal guardians Collected data: Study design demographic: age, gender, height, weight, body surface area clinical: indication for VKA therapy therapeutic: associated medications, weekly VKA maintenance dose biological: INR values during the follow-up genetic: VKORC1, CYP2C9, CYP4F2 polymorphisms unrelated patients enrolled: warfarin, fluindione, 2 acenocoumarol

8 Characteristics of the 83 warfarin treated patients Weekly maintenance dose (mg) Age (y) Sex (M/F) Weight (kg) Height (cm) Target INR 2.2 total cavopulmonary derivation 2.5 aortic valve replacement, dilated cardiomyopathy, coronary aneurysms after Kawasaki disease stroke with cyanotic congenital heart disease pulmonary arterial hypertension arrhythmia extra-cardiac diseases 3.3 mitral valve replacement N (%) or mean ± SD 23.2 ± 15.0 (3,5-84) 8.4 ± 5.6 (3 mo-18 y, median 9 y) 46/37 29 ± 20 (4-82) 121 ± 33 (50-183) 31 (37) 38 (46) 10 (12) 14 (17) 3 (4) 2 (2) 1 (1) 4 (5) 4 (5) 14 (17)

9 Influence of non-genetic variables on weekly warfarin maintenance dose univariate analysis p<0.05 height (p<.0001) weight (p<.0001) age (p=0.0014) gender (p=0.0082) 0.05 p 0.20 target INR (p=0.141) are associated with the weekly maintenance dose (mg) Weekly warfarin dose (mg) Height (cm) R 2 =0.4812

10 Influence of genetic variables on weekly warfarin maintenance dose univariate analysis VKORC1 genotype (p<.0001) and CYP2C9 genotype (p=0.1582) are associated with the warfarin maintenance dose (mg/week) 80 P <.0001 P=0.03 P= GG GA AA WT hetero homo mut VKORC1 genotype

11 Model for predicting the warfarin maintenance dose in children Overall interindividual variability Part of the variability (R 2 ) Height Target INR VKORC1 genotype CYP2C9 genotype 69.7 % 48.1 % 4.4 % 18.2 % 2.1% multivariate univariate Stepwise linear multiple regression: final model Dose (mg/week) = -10,77 + (0.28 x Height (cm)) - (5.44 x nb of VKORC1 variant allele(s) + (7.83 if target INR 2.5 or if target INR 3.3) (3.29 x nb CYP2C9 variant allele(s) )

12 Accuracy of the model Frequency (%) Difference (mg/week) (observed weekly dose-predicted weekly dose)

13 Accuracy of the model Frequency (%) Difference (mg/week) (observed weekly dose-predicted weekly dose) The difference between the observed weekly maintenance dose and the maintenance dose predicted individually by the model was 7mg/week in about 90% of patients

14 Discussion % of dose variability Nowack Nowack (n=34, (n=34, 15 ans) 15 y) Blood 2010 Children Moreau Moreau (n=83, (n=83, 9 ans) 9 y) Blood 2012 Biss Biss (n=120, (n=120, 11 ans) 11 y) Blood 2012 Middle-aged adults Takeushi Takeushi (n=1053, (n=1053, ans) y) Plos Genet 2009 Indication Gender Height Age CYP4F2 CYP2C9 VKORC1 Major influence of genetic factors in dose variability Developmental changes related to age: most important contributors to variations in warfarin dose requirement in children

15 Discussion Age (years) Weight (kg) Height (cm) Weightadjusted dose (ACCP,Chest 2008, 0.2mg/kg)) Predicted dose by Height only Predicted dose by our model including Pharmacogenetics Observed dose ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.5

16 Discussion Age (years) Weight (kg) Height (cm) Weightadjusted dose (ACCP,Chest 2008, 0.2mg/kg)) Predicted dose by Height only Predicted dose by our model including Pharmacogenetics Observed dose ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.5

17 Discussion Age (years) Weight (kg) Height (cm) Weightadjusted dose (ACCP,Chest 2008, 0.2mg/kg)) Predicted dose by Height only Predicted dose by our model including Pharmacogenetics Observed dose ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.5

18 Discussion Age (years) Weight (kg) Height (cm) Weightadjusted dose (ACCP,Chest 2008, 0.2mg/kg)) Predicted dose by Height only Predicted dose by our model including Pharmacogenetics Observed dose ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.5 Need to make individual dose adjustments Development of a nomogram especially for children in progress

19 Conclusion Our dosing model based on Height, Target INR and VKORC1 and CYP2C9 genotypes explain 70% of the dose variability, the overall contribution of genetic factors being 20%. Our model predicted the warfarin maintenance dose within 1mg/day in around 90% of children. Further work is needed to determine whether this model could minimize the risk or over- and under-anticoagulation. Clinical guidelines integrating genetic factors could improve the efficacy and safety of warfarin treatment in children.

20 Acknowledgements Fédération Française de Cardiologie Société Française de Cardiologie Damien Bonnet, Hôpital Necker-Enfants Malades Dominique Lasne, Hôpital Necker-Enfants Malades Marie-Anne Loriot, Hôpital Européen Georges Pompidou Virginie Siguret, Hôpital Européen Georges Pompidou Jean-Louis Golmard, Hôpital de la Pitié Salpêtrière Caroline Elie, Hôpital Necker-Enfants Malades Radhia Cheurfi, Hôpital Necker-Enfants Malades

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22 Influence of genetic and non-genetic variables on the time spent within, above and below the pre-specified INR ranges INR ranges for which the physicians did not systematically perform a dosage adjustment Of the 83 patients, 61 had INR values collected routinely (mean follow-up 388 ± 229 days): 83.0% ± 14.6% within the INR range 9.6% ± 10.5% above the range 7.1 ± 8.9 below the range

23 Influence of genetic and non-genetic variables on the time spent within, above and below the pre-specified INR ranges INR ranges for which the physicians did not systematically perform a dosage adjustment Of the 83 patients, 61 had INR values collected routinely (mean follow-up 388 ± 229 days): 83.0% ± 14.6% within the INR range 9.6% ± 10.5% above the range 7.1 ± 8.9 below the range Neither genetic nor non-genetic variables was significantly (multivariate analysis) associated with the times spent within, above and below the therapeutic range

24 Characteristics of the 83 warfarin treated patients Weekly maintenance dose (mg) Age (y) Sex (M/F) Weight (kg) Height (cm) Target INR 2,2 2,5 3,3 VKORC1 Genotype GG GA AA CYP2C9 Genotype *1/*1 *1/*x *x/*x CYP4F2 Genotype CC CT TT N (%) or mean ± SD 23,2 ± 15,0 (3,5-84) 8,4 ± 5,6 (3 mo-18 y, median 9 years) 46/37 29 ± 20 (4-82) 121 ± 33 (50-183) 31 (37) 38 (46) 14 (17) 25 (30) 43 (52) 15 (18) 53 (64) 25 (30) 5 (6) 46 (55) 26 (31) 9 (11)

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