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Informing Pharmacok...
Informing Pharmacokinetic Models With Physiological Data: Oral Population Modeling of L-Serine in Humans
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- Bosley, J. R. (author)
- Clermont Bosley LLC, Philadelphia, PA 19348 USA.
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- Björnson, Elias, 1988 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Chalmers tekniska högskola,Chalmers University of Technology,Sahlgrenska universitetssjukhuset,Sahlgrenska University Hospital,Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden.;Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden.
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- Zhang, C. (author)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi
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- Turkez, H. (author)
- Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey.
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- Nielsen, Jens B, 1962 (author)
- Chalmers tekniska högskola,Chalmers University of Technology,Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden.
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- Uhlén, Mathias (author)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi
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- Borén, Jan, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Sahlgrenska universitetssjukhuset,Sahlgrenska University Hospital,Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey.
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- Mardinoglu, Adil, 1982 (author)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England.
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Clermont Bosley LLC, Philadelphia, PA 19348 USA Institutionen för medicin, avdelningen för molekylär och klinisk medicin (creator_code:org_t)
- 2021-05-13
- 2021
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
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Abstract
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- To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- NATURVETENSKAP -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)
- NATURAL SCIENCES -- Computer and Information Sciences -- Bioinformatics (hsv//eng)
- NATURVETENSKAP -- Matematik -- Sannolikhetsteori och statistik (hsv//swe)
- NATURAL SCIENCES -- Mathematics -- Probability Theory and Statistics (hsv//eng)
Keyword
- Pharmacokinectics
- L-Serine (ser)
- systems biology
- NAFLD (non alcoholic
- fatty liver disease)
- oral supplementation
- amino-acid-metabolism
- plasma
- safety
- mice
- Pharmacology & Pharmacy
- Pharmacokinectics
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Bosley, J. R.
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Björnson, Elias, ...
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Zhang, C.
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Turkez, H.
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Nielsen, Jens B, ...
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Uhlén, Mathias
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show more...
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Borén, Jan, 1963
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Mardinoglu, Adil ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Computer and Inf ...
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and Bioinformatics
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Mathematics
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and Probability Theo ...
- Articles in the publication
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Frontiers in Pha ...
- By the university
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University of Gothenburg
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Chalmers University of Technology
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Royal Institute of Technology