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UNPRESENTED POSTER Personalization of the Insulin Dose-Response Relationship in T2DM using a PP-QSP Model of T2DM and Individual Sampling of C-Peptide Levels #296
BACKGROUND: Insulin secretion rate cannot be estimated from insulin concentrations alone, as hepatic extraction varies between subjects. Plasma concentrations of c-peptide can be used as a marker for insulin secretion.
METHODS: A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model of insulin and c-peptide was developed with the Open Systems Pharmacology Suite (OSPS). C-peptide kinetics were fitted to PK data following i.v. infusion. The insulin receptor (IR) submodel was fitted to in vitro data of receptor internalization and phosphorylation. IR distribution in tissues was fitted to fractional insulin extraction and interstitial/plasma concentration ratios.
RESULTS: C-peptide is secreted pancreas and eliminated by the liver (12%) and renally through glomerular filtration and tubular secretion. A fraction unbound of 30% was assumed to describe the bolus administration. Insulin is secreted with the same rate as c peptide, filtered in the kidney, and eliminated in liver, fat, muscle, and kidney tissues after binding to the IR. The IR model captures insulin binding, complex internalization, and the phosphorylation of IR substrate (IRS) 1. The model describes the observed time-courses of IR and IRS1 phosphorylation.
CONCLUSION: The combination of the c-peptide and insulin models allows for individualization of the secretory capacity based on c-peptide data, capturing the various states of T2DM disease progression. The IR model mechanistically translates the plasma insulin concentrations to the anticipated pharmacodynamic effect, including time delays and non linearities. The physiology database of the PBPK backbone and the information on the variability and changes in parameters of glucose regulation will enable personalized prediction of disease progression and of individual treatment outcome within a chosen population.
JanSchlender
commented
3 years ago
ASCPT 2021 P. Balazki, S. Schaller, T. Lehr
BACKGROUND: Insulin secretion rate cannot be estimated from insulin concentrations alone, as hepatic extraction varies between subjects. Plasma concentrations of c-peptide can be used as a marker for insulin secretion. METHODS: A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model of insulin and c-peptide was developed with the Open Systems Pharmacology Suite (OSPS). C-peptide kinetics were fitted to PK data following i.v. infusion. The insulin receptor (IR) submodel was fitted to in vitro data of receptor internalization and phosphorylation. IR distribution in tissues was fitted to fractional insulin extraction and interstitial/plasma concentration ratios. RESULTS: C-peptide is secreted pancreas and eliminated by the liver (12%) and renally through glomerular filtration and tubular secretion. A fraction unbound of 30% was assumed to describe the bolus administration. Insulin is secreted with the same rate as c peptide, filtered in the kidney, and eliminated in liver, fat, muscle, and kidney tissues after binding to the IR. The IR model captures insulin binding, complex internalization, and the phosphorylation of IR substrate (IRS) 1. The model describes the observed time-courses of IR and IRS1 phosphorylation. CONCLUSION: The combination of the c-peptide and insulin models allows for individualization of the secretory capacity based on c-peptide data, capturing the various states of T2DM disease progression. The IR model mechanistically translates the plasma insulin concentrations to the anticipated pharmacodynamic effect, including time delays and non linearities. The physiology database of the PBPK backbone and the information on the variability and changes in parameters of glucose regulation will enable personalized prediction of disease progression and of individual treatment outcome within a chosen population.