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| 2. |
- Hamberg, Anna-Karin, et al.
(författare)
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Characterising variability in warfarin dose requirements in children using modelling and simulation
- 2013
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 78:1, s. 158-169
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimise a published adult pharmacometric warfarin model for use in children.RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.
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| 3. |
- Hamberg, Anna-Karin, et al.
(författare)
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Predicting the relative importance of genetic, clinical and demographic factors on warfarin dose in children using pharmacometric modelling
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- It is difficult to predict anticoagulation response to warfarin in children mainly because of a wide inter-individual variability in warfarin dose requirement. The present study objective was to identify important predictors of dose in children and to optimize a previous NONMEM warfarin model for a priori and a posteriori dose and INR predictions in children. Data from 163 warfarin treated children with underlying heart disease (median age 6.3 years) were used. CYP2C9 and VKORC1 genotype caused up to 4-fold and 2-fold differences in warfarin dose requirement, respectively. Other important predictors of warfarin dose were bodyweight, age, baseline and target INR, and time since initiation of therapy with lower doses during the initiation. CYP4F2 genotype had only a marginal effect on dose. The present study findings will aid the development of a personalised approach to warfarin therapy in children, in the pursuit of improving both efficacy and safety of anticoagulation therapy.
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| 4. |
- Marvig, Camilla L., et al.
(författare)
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Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants
- 2015
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 136:1, s. 69-75
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. Materials and Methods: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged > 18 years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. Results: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3 months treatment period, patients experienced an improvement (p < 0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p < 0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. Conclusions: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3 months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.
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| 6. |
- Pirmohamed, Munir, et al.
(författare)
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A Randomized Trial of Genotype-Guided Dosing of Warfarin
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 369:24, s. 2294-2303
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Tidskriftsartikel (refereegranskat)abstract
- Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639GA) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR 4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy.
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| 8. |
- Pirmohamed, Munir, et al.
(författare)
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Oral anticoagulation : a critique of recent advances and controversies
- 2015
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 36:3, s. 153-163
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Forskningsöversikt (refereegranskat)abstract
- There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.
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| 9. |
- Takeuchi, Masanobu, et al.
(författare)
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CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose : a systematic review and meta-analysis
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 20:2, s. 306-319
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Forskningsöversikt (refereegranskat)abstract
- Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I-2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I-2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I-2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
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| 10. |
- van Schie, Rianne M. F., et al.
(författare)
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Genotype-guided dosing of coumarin derivatives : the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design
- 2009
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 10:10, s. 1687-1695
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Tidskriftsartikel (refereegranskat)abstract
- The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.
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