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- Krekels, Elke H. J., et al.
(author)
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Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial
- 2016
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In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 55:9, s. 1079-1090
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Journal article (peer-reviewed)abstract
- Introduction: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.Methods: Model development was performed using NONMEMA (R) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance.Results: A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance.Conclusion: Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (aecurrency sign60 kg), moderate renal impairment (CLCR aecurrency sign50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.
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| 2. |
- Nyberg, Joakim, 1978-, et al.
(author)
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Edoxaban Exposure-Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism
- 2016
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In: CPT. - : Wiley. - 2163-8306. ; 5:4, s. 222-232
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Journal article (peer-reviewed)abstract
- Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (C-av) (HRCav) 50.98 (i.e., change in the HR with every 1 ng/mL increase of C-av); the composite of recurrent DVT and nonfatal PE with HRC(av)50.99; and the composite of recurrent DVT, nonfatal PE, and all-cause mortality HRC(av)50.98, and all death using maximal edoxaban concentration (C-max) with HR (C-max) 50.99. No statistical significant exposure-response relationships were found for clinically relevant bleeding or major adverse cardiovascular event. Results support the recommendation of once-daily edoxaban 60 mg, and a reduced 30 mg dose in patients with moderate renal impairment, body weight <= 60 kg, or use of P-glycoprotein inhibitors verapamil or quinidine.
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| 3. |
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| 4. |
- Zheng, Hou-Feng, et al.
(author)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Journal article (peer-reviewed)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 5. |
- Berggren, Martin, et al.
(author)
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Allochthony in major groups of crustacean zooplankton in boreal lakes – strongly contrasting patterns across space and time
- 2015
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Conference paper (other academic/artistic)abstract
- The role of terrestrial organic carbon for recipient aquatic ecosystems is intensively researched. A multitude of studies now show that terrestrially-derived carbon supports a significant share (allochthony) of consumer biomass in many freshwaters. However, little is known about the mechanisms by which terrestrially-derived carbon is transferred to the level of metazoan zooplankton, and whether these pathways vary among taxonomic and functional groups. Here we present stable isotope-inferred allochthony in three major groups of crustacean zooplankton – Cladocera, Calanoida and Cyclopoida – measured both seasonally and across wide ranges of environmental gradients in boreal areas of Canada and Sweden. Our data show strongly contrasting patterns between taxa in the allochthony regulation. Whereas allochthony in calanoids was regulated by shortage of phytoplankton particles per se, both across space and time, allochthony in cyclopoids was related to food chains supported by dissolved organic carbon. Cladocerans showed the highest allochthony, but a more complex regulation. Terrestrial organic matter can be an important resource for cyclopoids and cladocerans on an annual basis, but it can also sustain otherwise herbivorous calanoids during low productivity conditions, e.g. in winter.
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| 6. |
- Creed, Irena F., et al.
(author)
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Global change-driven effects on dissolved organic matter composition : Implications for food webs of northern lakes
- 2018
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 24:8, s. 3692-3714
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Research review (peer-reviewed)abstract
- Northern ecosystems are experiencing some of the most dramatic impacts of global change on Earth. Rising temperatures, hydrological intensification, changes in atmospheric acid deposition and associated acidification recovery, and changes in vegetative cover are resulting in fundamental changes in terrestrial-aquatic biogeochemical linkages. The effects of global change are readily observed in alterations in the supply of dissolved organic matter (DOM)-the messenger between terrestrial and lake ecosystems-with potentially profound effects on the structure and function of lakes. Northern terrestrial ecosystems contain substantial stores of organic matter and filter or funnel DOM, affecting the timing and magnitude of DOM delivery to surface waters. This terrestrial DOM is processed in streams, rivers, and lakes, ultimately shifting its composition, stoichiometry, and bioavailability. Here, we explore the potential consequences of these global change-driven effects for lake food webs at northern latitudes. Notably, we provide evidence that increased allochthonous DOM supply to lakes is overwhelming increased autochthonous DOM supply that potentially results from earlier ice-out and a longer growing season. Furthermore, we assess the potential implications of this shift for the nutritional quality of autotrophs in terms of their stoichiometry, fatty acid composition, toxin production, and methylmercury concentration, and therefore, contaminant transfer through the food web. We conclude that global change in northern regions leads not only to reduced primary productivity but also to nutritionally poorer lake food webs, with discernible consequences for the trophic web to fish and humans.
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| 7. |
- Said Al-Kharusi, Enass, et al.
(author)
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Mapping conservation priorities in alpine and subartctic Swedish lakes affected by rapid climate change
- 2018
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Conference paper (other academic/artistic)abstract
- Swedish alpine and subarctic areas undergo rapid transitions due to climate change, especially in relatively humid areas where the forest vegetation is expanding. It has been suggested that lakes in these areas are in transition from clearwater into brownwater state, because of the humus layer building up in surrounding soils, with negative consequences, e.g., for the biomass production of zooplankton and fish. However, this idea remains a hypothesis to be tested at a large scale. We used the new high-resolution satellite Sentinel-2 to evaluate the relationship between lake color and forest succession in 250 widely distributed lakes across Sweden. Preliminary results show that lakes remain surprisingly clear in areas of recent forest expansion, suggesting that there is lag time before brownification occurs. Our study could be used to map regions that are sensitive to future water brownification.
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