| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Province, M. A., et al.
(författare)
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CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - New York, USA : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 95:2, s. 216-227
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Tidskriftsartikel (refereegranskat)abstract
- The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
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| 3. |
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| 4. |
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| 5. |
- Björkman, Sven, et al.
(författare)
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Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults : the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring
- 2010
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 8:4, s. 730-736
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient. OBJECTIVES: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing. PATIENTS: Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < or = 2 IU dL(-1)) in three clinical studies were included. RESULTS: In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment. CONCLUSION: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.
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| 6. |
- Björkman, Sven, et al.
(författare)
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Population pharmacokinetics of recombinant factor VIII : the relationships of pharmacokinetics to age and body weight
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:2, s. 612-618
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Tidskriftsartikel (refereegranskat)abstract
- Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.
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| 7. |
- Collins, P. W., et al.
(författare)
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Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A
- 2009
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 7:3, s. 413-420
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1). Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate. OBJECTIVES: To assess the effect of FVIII level on break-through bleeding in patients with severe hemophilia A on prophylaxis. PATIENTS/METHODS: This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII <1 IU dL(-1)) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). RESULTS: The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. Conclusions: These data have important implications for the management of patients with severe hemophilia.
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| 8. |
- Collins, P. W., et al.
(författare)
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Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A : influences of variance in pharmacokinetics and treatment regimens
- 2010
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Ingår i: Journal of Thrombosis and Haemostasis. - : International Society on Thrombosis and Haemostasis. - 1538-7933 .- 1538-7836. ; 8:2, s. 269-275
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. OBJECTIVES: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter-patient variability in pharmacokinetics and different dosing regimens on trough levels. METHODS: Simulations used FVIII half-lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. RESULTS AND CONCLUSIONS: Half-life and dose frequency had a larger effect on trough FVIII and time per week with FVIII<1 IU dL(-1) than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter-patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg(-1) and some would require more than 400 IU kg(-1). Knowledge of individual patients' half-lives and alteration of frequency of infusions may allow the more cost-effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.
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| 9. |
- Isles, Peter D. F., et al.
(författare)
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Climate-driven changes in energy and mass inputs systematically alter nutrient concentration and stoichiometry in deep and shallow regions of Lake Champlain
- 2017
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Ingår i: Biogeochemistry. - : SPRINGER. - 0168-2563 .- 1573-515X. ; 133:2, s. 201-217
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Tidskriftsartikel (refereegranskat)abstract
- Concentrations of nitrogen (N) and phosphorus (P) in lakes may be differentially impacted by climate-driven changes in nutrient loading and by direct impacts of temperature and wind speed on internal nutrient cycling. Such changes may result in systematic shifts in lake N:P under future climate warming. We used 21 years of monitoring data to compare long-term and intra-annual trends in total N (TN), total P (TP) and TN:TP at 15 sites in Lake Champlain to concurrent measurements of watershed nutrient inputs and meteorological drivers. TN:TP declined sharply lake-wide, particularly in the past decade, yet the drivers of this trend varied based on site depth. In deep sites, declines were driven by changes in watershed loading of dissolved P and N and (in some cases) by decreases in hypolimnetic dissolved oxygen. In shallow sites, declines in TN:TP were primarily driven by long-term increases in temperature and decreases in wind speed, and exhibited systematic seasonal variability in TN:TP due to the timing of sediment P loading, N removal processes, and external nutrient inputs. We developed a conceptual model to explain the observed trends, and suggest that while climate drivers have affected nutrient dynamics in shallow and deep sites differently, both deep and shallow sites are likely to experience further declines in N:P and increases in cyanobacteria dominance if recent climate trends continue.
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| 10. |
- Isles, Peter D. F., et al.
(författare)
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Modeling the drivers of interannual variability in cyanobacterial bloom severity using self-organizing maps and high-frequency data
- 2017
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Ingår i: Inland Waters. - : TAYLOR & FRANCIS LTD. - 2044-2041 .- 2044-205X. ; 7:3, s. 333-347
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that cyanobacteria populations in shallow lakes exhibit dramatic fluctuations on both interannual and intraannual timescales; however, despite extensive research, disentangling the drivers of interannual variability in bloom severity has proved challenging. Critical thresholds of abiotic drivers such as wind, irradiance, air temperature, and tributary inputs may control the development and collapse of blooms, but these thresholds are difficult to identify in large and complex datasets. In this study, we compared high-frequency estimates of oxygen metabolism in a shallow bay of Lake Champlain to concurrent measurements of physical and chemical parameters over 3 years with very different bloom dynamics. We clustered the data using supervised and unsupervised self-organizing maps to identify the environmental drivers associated with key stages of bloom development. We then used threshold analysis to identify subtle yet important thresholds of thermal stratification that drive transitions between bloom growth and decline. We found that extended periods with near-surface temperature differentials above 0.20 degrees C were associated with the initial development of bloom conditions, and subsequent frequency and timing of wind mixing events had a strong influence on interannual variability in bloom severity. The methods developed here can be widely applied to other high frequency lake monitoring datasets to identify critical thresholds controlling bloom development.
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