Quantitative systems pharmacology of interferon alpha administration : A multi-scale approach

The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different phy...
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Autor*in:	Kalra, Priyata [verfasserIn] Sahle, Sven [verfasserIn] Kummer, Ursula - 1967- [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	February 13, 2019

Schlagwörter:	Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling

Anmerkung:	Gesehen am 31.07.2019
Umfang:	21

Übergeordnetes Werk:	Enthalten in: PLOS ONE - San Francisco, California, US : PLOS, 2006, 14(2019,2) Artikel-Nummer e0209587, 21 Seiten
Übergeordnetes Werk:	volume:14 ; year:2019 ; number:2 ; extent:21

Links:	Volltext Volltext

DOI / URN:	10.1371/journal.pone.0209587

Katalog-ID:	1670318621

Internformat


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245	1	0	\|a Quantitative systems pharmacology of interferon alpha administration \|b A multi-scale approach \|c Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer
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allfields	10.1371/journal.pone.0209587 doi (DE-627)1670318621 (DE-599)KXP1670318621 (OCoLC)1341235110 DE-627 ger DE-627 rda eng Kalra, Priyata verfasserin (DE-588)1181381096 (DE-627)1662669690 aut Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer February 13, 2019 21 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.07.2019 The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling Sahle, Sven verfasserin (DE-588)1099116783 (DE-627)85782452X (DE-576)46921466X aut Kummer, Ursula 1967- verfasserin (DE-588)115411682 (DE-627)691297975 (DE-576)176480897 aut Enthalten in PLOS ONE San Francisco, California, US : PLOS, 2006 14(2019,2) Artikel-Nummer e0209587, 21 Seiten Online-Ressource (DE-627)523574592 (DE-600)2267670-3 (DE-576)281331979 1932-6203 nnns volume:14 year:2019 number:2 extent:21 https://doi.org/10.1371/journal.pone.0209587 Verlag Resolving-System Volltext https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 2 21 14(2019,2) Artikel-Nummer e0209587, 21 Seiten 2013 01 DE-16-250 3501649576 00 --%%-- --%%-- --%%-- --%%-- l01 31-07-19 2013 01 DE-16-250 00 s hd2019 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_8 2013 01 DE-16-250 03 s s_21 2013 01 DE-16-250 04 p (DE-627)1663673411 Kalra, Priyata 2013 01 DE-16-250 04 k (DE-627)1416535500 Fakultät für Biowissenschaften 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1539213579 Sahle, Sven 2013 01 DE-16-250 05 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_6 2013 01 DE-16-250 06 p (DE-627)1497999472 Kummer, Ursula 2013 01 DE-16-250 06 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_8
spelling	10.1371/journal.pone.0209587 doi (DE-627)1670318621 (DE-599)KXP1670318621 (OCoLC)1341235110 DE-627 ger DE-627 rda eng Kalra, Priyata verfasserin (DE-588)1181381096 (DE-627)1662669690 aut Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer February 13, 2019 21 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.07.2019 The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling Sahle, Sven verfasserin (DE-588)1099116783 (DE-627)85782452X (DE-576)46921466X aut Kummer, Ursula 1967- verfasserin (DE-588)115411682 (DE-627)691297975 (DE-576)176480897 aut Enthalten in PLOS ONE San Francisco, California, US : PLOS, 2006 14(2019,2) Artikel-Nummer e0209587, 21 Seiten Online-Ressource (DE-627)523574592 (DE-600)2267670-3 (DE-576)281331979 1932-6203 nnns volume:14 year:2019 number:2 extent:21 https://doi.org/10.1371/journal.pone.0209587 Verlag Resolving-System Volltext https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 2 21 14(2019,2) Artikel-Nummer e0209587, 21 Seiten 2013 01 DE-16-250 3501649576 00 --%%-- --%%-- --%%-- --%%-- l01 31-07-19 2013 01 DE-16-250 00 s hd2019 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_8 2013 01 DE-16-250 03 s s_21 2013 01 DE-16-250 04 p (DE-627)1663673411 Kalra, Priyata 2013 01 DE-16-250 04 k (DE-627)1416535500 Fakultät für Biowissenschaften 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1539213579 Sahle, Sven 2013 01 DE-16-250 05 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_6 2013 01 DE-16-250 06 p (DE-627)1497999472 Kummer, Ursula 2013 01 DE-16-250 06 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_8
allfields_unstemmed	10.1371/journal.pone.0209587 doi (DE-627)1670318621 (DE-599)KXP1670318621 (OCoLC)1341235110 DE-627 ger DE-627 rda eng Kalra, Priyata verfasserin (DE-588)1181381096 (DE-627)1662669690 aut Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer February 13, 2019 21 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.07.2019 The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling Sahle, Sven verfasserin (DE-588)1099116783 (DE-627)85782452X (DE-576)46921466X aut Kummer, Ursula 1967- verfasserin (DE-588)115411682 (DE-627)691297975 (DE-576)176480897 aut Enthalten in PLOS ONE San Francisco, California, US : PLOS, 2006 14(2019,2) Artikel-Nummer e0209587, 21 Seiten Online-Ressource (DE-627)523574592 (DE-600)2267670-3 (DE-576)281331979 1932-6203 nnns volume:14 year:2019 number:2 extent:21 https://doi.org/10.1371/journal.pone.0209587 Verlag Resolving-System Volltext https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 2 21 14(2019,2) Artikel-Nummer e0209587, 21 Seiten 2013 01 DE-16-250 3501649576 00 --%%-- --%%-- --%%-- --%%-- l01 31-07-19 2013 01 DE-16-250 00 s hd2019 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_8 2013 01 DE-16-250 03 s s_21 2013 01 DE-16-250 04 p (DE-627)1663673411 Kalra, Priyata 2013 01 DE-16-250 04 k (DE-627)1416535500 Fakultät für Biowissenschaften 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1539213579 Sahle, Sven 2013 01 DE-16-250 05 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_6 2013 01 DE-16-250 06 p (DE-627)1497999472 Kummer, Ursula 2013 01 DE-16-250 06 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_8
allfieldsGer	10.1371/journal.pone.0209587 doi (DE-627)1670318621 (DE-599)KXP1670318621 (OCoLC)1341235110 DE-627 ger DE-627 rda eng Kalra, Priyata verfasserin (DE-588)1181381096 (DE-627)1662669690 aut Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer February 13, 2019 21 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.07.2019 The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling Sahle, Sven verfasserin (DE-588)1099116783 (DE-627)85782452X (DE-576)46921466X aut Kummer, Ursula 1967- verfasserin (DE-588)115411682 (DE-627)691297975 (DE-576)176480897 aut Enthalten in PLOS ONE San Francisco, California, US : PLOS, 2006 14(2019,2) Artikel-Nummer e0209587, 21 Seiten Online-Ressource (DE-627)523574592 (DE-600)2267670-3 (DE-576)281331979 1932-6203 nnns volume:14 year:2019 number:2 extent:21 https://doi.org/10.1371/journal.pone.0209587 Verlag Resolving-System Volltext https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 2 21 14(2019,2) Artikel-Nummer e0209587, 21 Seiten 2013 01 DE-16-250 3501649576 00 --%%-- --%%-- --%%-- --%%-- l01 31-07-19 2013 01 DE-16-250 00 s hd2019 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_8 2013 01 DE-16-250 03 s s_21 2013 01 DE-16-250 04 p (DE-627)1663673411 Kalra, Priyata 2013 01 DE-16-250 04 k (DE-627)1416535500 Fakultät für Biowissenschaften 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1539213579 Sahle, Sven 2013 01 DE-16-250 05 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_6 2013 01 DE-16-250 06 p (DE-627)1497999472 Kummer, Ursula 2013 01 DE-16-250 06 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_8
allfieldsSound	10.1371/journal.pone.0209587 doi (DE-627)1670318621 (DE-599)KXP1670318621 (OCoLC)1341235110 DE-627 ger DE-627 rda eng Kalra, Priyata verfasserin (DE-588)1181381096 (DE-627)1662669690 aut Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer February 13, 2019 21 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.07.2019 The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling Sahle, Sven verfasserin (DE-588)1099116783 (DE-627)85782452X (DE-576)46921466X aut Kummer, Ursula 1967- verfasserin (DE-588)115411682 (DE-627)691297975 (DE-576)176480897 aut Enthalten in PLOS ONE San Francisco, California, US : PLOS, 2006 14(2019,2) Artikel-Nummer e0209587, 21 Seiten Online-Ressource (DE-627)523574592 (DE-600)2267670-3 (DE-576)281331979 1932-6203 nnns volume:14 year:2019 number:2 extent:21 https://doi.org/10.1371/journal.pone.0209587 Verlag Resolving-System Volltext https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587 Verlag Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 2 21 14(2019,2) Artikel-Nummer e0209587, 21 Seiten 2013 01 DE-16-250 3501649576 00 --%%-- --%%-- --%%-- --%%-- l01 31-07-19 2013 01 DE-16-250 00 s hd2019 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_8 2013 01 DE-16-250 03 s s_21 2013 01 DE-16-250 04 p (DE-627)1663673411 Kalra, Priyata 2013 01 DE-16-250 04 k (DE-627)1416535500 Fakultät für Biowissenschaften 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1539213579 Sahle, Sven 2013 01 DE-16-250 05 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_6 2013 01 DE-16-250 06 p (DE-627)1497999472 Kummer, Ursula 2013 01 DE-16-250 06 k (DE-627)1416737987 Centre for Organismal Studies Heidelberg (COS) 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_8
language	English
source	Enthalten in PLOS ONE 14(2019,2) Artikel-Nummer e0209587, 21 Seiten volume:14 year:2019 number:2 extent:21
sourceStr	Enthalten in PLOS ONE 14(2019,2) Artikel-Nummer e0209587, 21 Seiten volume:14 year:2019 number:2 extent:21
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topic_facet	Blood plasma Drug administration Hepatocytes Interferons Intracellular receptors Pharmacokinetics Pharmacology Simulation and modeling
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title	Quantitative systems pharmacology of interferon alpha administration A multi-scale approach
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title_full	Quantitative systems pharmacology of interferon alpha administration A multi-scale approach Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer
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title_sub	A multi-scale approach
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title_sort	quantitative systems pharmacology of interferon alpha administrationa multi-scale approach
title_auth	Quantitative systems pharmacology of interferon alpha administration A multi-scale approach
abstract	The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Gesehen am 31.07.2019
abstractGer	The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Gesehen am 31.07.2019
abstract_unstemmed	The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Gesehen am 31.07.2019
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title_short	Quantitative systems pharmacology of interferon alpha administration
url	https://doi.org/10.1371/journal.pone.0209587 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587
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up_date	2024-07-05T02:36:06.375Z
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