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- Ayoun Alsoud, Rami, et al.
(författare)
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Model-based interspecies scaling for predicting human pharmacokinetics of CB 4332, a complement factor I protein
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The extrapolation of a protein pharmacokinetics (PK) from preclinical to clinical studies can be less reliable than for small molecules. CB 4332 is a 150 kDa recombinant complement factor I (CFI) protein. In order to support clinical development, interspecies scaling of CB 4332 using traditional and model-based approaches was performed to inform first-in-human (FIH) dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous (i.v.) and subcutaneous (s.c.) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modelling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. Using the traditional dose-by-factor approach, a maximum recommended starting s.c. dose of 0.9 mg/kg once weekly was calculated using the NOAEL observed in NHPs. The model-based clinical trial simulations predicted it to result in a trough concentration at steady state 12.8% of the determined efficacy target for CB 4332 in humans. Interspecies scaling was performed for CB 4332 using traditional and model-based scaling, where PK modeling allowed the inclusion of preclinical PK information from three species, accounted for potential effects of ADA and species differences in elimination, and allowed the prediction of human PK for FIH dose selection.
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| 2. |
- Puts, Isolde Callisto, 1988-
(författare)
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Impacts of global change on primary production in northern lakes
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Algae are primary producers, a major component of the aquatic foodweb, and changes in primary production affect aquatic ecology in general. Global changes such as warming, recovery of acidification and changes in land-use have caused warming and browning of northern lakes. Warming is a direct effect of increasing air temperatures, whereas browning is mainly caused by increasing amounts of terrestrially derived colored dissolved organic carbon (DOC). Altogether, such global changes impact important environmental drivers for aquatic gross primary production (GPP). Increased temperatures and nutrient supplementation by DOC at low concentrations enhance GPP, but the browning by DOC at high concentrations inhibits GPP by light reduction, resulting in contrasting controls of global changes on primary production in northern lakes. Primary producers grow in two distinct habitats; free-floating algae (phytoplankton) and stationary periphytic (attached) algae that are restricted to use the light that reaches them. Periphyton includes algae growing on submerged surfaces ranging from nutrient-poor rocks to nutrient-rich sediments (here: benthic algae), and both often exceed pelagic GPP but are overlooked and often simply excluded from algal biomass estimates.In this thesis, I investigate how global change influences key environmental drivers of GPP, and how those changes impact GPP in the benthic and pelagic habitat, and the sum and partitioning of GPP between these habitats (the autrotrophic structuring). I do this by interpreting a dataset with GPP measurements in several lakes over the Swedish Arctic, subarctic and boreal landscape that representa wide range of DOC concentrations. I also assess to what extent temperature and DOC impact periphytic algae growth on plastic strips in an experimental study where DOC and temperature are manipulated in 20 ponds. Besides assessing the direct impacts of changes in nutrients and light climate associated with changes in DOC, I assess indirect impacts of global changes on primary production, e.g., through intensified warming, CO2 supersaturation, changes in pH, and the role of landscape processes and properties.Results confirm that DOC is dominant in structuring GPP in northern lakes by light inhibition, nutrient supplementation, indirect warming of surface waters, and additionally by CO2 fertilization. In addition, warming can enhance growth rates, but thermal compensation can also lead to reduced algae growth. Moreover, periphytic GPP of algae growing on both soft nutrient-rich sediments and nutrient-poor plastic strips GPP was generally much higher than pelagic GPP, and should thus not be excluded in studies assessing global change impacts on GPP. DOC affects the total GPP, as well as the autotrophic structuring in northern lakes, and likely also higher trophic levels productivity and community composition.
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