Pharmacokinetic and pharmacodynamic re-evaluation of a genetic-guided warfarin trial
| العنوان: | Pharmacokinetic and pharmacodynamic re-evaluation of a genetic-guided warfarin trial |
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| المؤلفون: | Francesca Groppa, Stefania Moz, Carlo Federico Zambon, Mario Plebani, Vittorio Pengo, Paola Fogar, Andrea Padoan, Dania Bozzato, Giovanni De Rosa, Roberto Padrini |
| المصدر: | European Journal of Clinical Pharmacology. 74:571-582 |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Genotype, medicine.drug_class, CYP4F2, Urology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Algorithm, Pharmacodynamic, Pharmacogenetics, Pharmacokinetics, Warfarin, Vitamin K Epoxide Reductases, Atrial Fibrillation, medicine, Humans, Pharmacology (medical), Cytochrome P450 Family 4, International Normalized Ratio, 030212 general & internal medicine, Precision Medicine, Aged, Cytochrome P-450 CYP2C9, Aged, 80 and over, Pharmacology, Maintenance dose, business.industry, Anticoagulant, Anticoagulants, General Medicine, Middle Aged, CTL, Quartile, Pharmacodynamics, Female, business, Algorithms, medicine.drug |
| الوصف: | A previous trial failed to demonstrate the superiority of a demographic-genetic algorithm in predicting warfarin (W) dose over a standard clinical approach. The purpose of the present study is to re-analyse the results in subgroups of patients with differing baseline sensitivity to W, integrated with additional pharmacokinetic data. The original trial allocated 180 treatment-naive patients with non-valvular atrial fibrillation to a control arm (CTL, n = 92) or a genetic-guided arm (GEN, n = 88). Before starting anticoagulation treatment, all patients were genotyped for CYP2C9, VKORC1 and CYP4F2 variants and classified into four quartiles (Q1, Q2, Q3, Q4) according to the algorithm-predicted W maintenance dose. International normalised ratios (INR) and plasma concentrations of S-warfarin [S-W]s and R-warfarin [R-W]s were measured at baseline and on days 5, 7, 9, 12, 15 and 19 of therapy. In the lowest dose quartile (Q1), the number of INRs > 3 and mean INR values on days 5 and 7 were significantly higher in CTL than in GEN. In Q3 and Q4, the mean INR values reached therapeutic level (> 2) 2 days later in CTL than in GEN. During follow-up, the mean time courses of INRs and [S-W]s in GEN were remarkably stable in all dose quartiles. Thus, mean changes from starting to final doses were significantly smaller in GEN than in CTL. Plasma concentrations of R-W (a partially active enantiomer) steadily increased from day 5 to day 19 in all Qs in both CTL and GEN, except in the Q1 CTL group, due to the marked dose reduction required. This analysis showed that the demographic-genetic algorithm used to predict the W dose can identify patients with differing degrees of sensitivity to W and to ‘normalise’ their average anticoagulant responses. The progressive rise in [R-W]s throughout the 19-day follow-up indicates that the (partial) contribution of R-W to the W anticoagulant effect changes continually during the early phase of treatment. |
| تدمد: | 1432-1041 0031-6970 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::12015610659e6e4f13554782912c5ad0Test https://doi.org/10.1007/s00228-018-2422-8Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....12015610659e6e4f13554782912c5ad0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14321041 00316970 |
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