Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
02
07
2018
accepted:
08
12
2018
entrez:
14
2
2019
pubmed:
14
2
2019
medline:
13
11
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30759154
doi: 10.1371/journal.pone.0209587
pii: PONE-D-18-19609
pmc: PMC6374012
doi:
Substances chimiques
Immunologic Factors
0
Interferon-alpha
0
STAT Transcription Factors
0
Janus Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0209587Déclaration de conflit d'intérêts
LK, TG, CN, JL are employees of Bayer Pharma, Germany. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Références
Nat Rev Immunol. 2013 Jul;13(7):535-42
pubmed: 23743475
Gastroenterology. 2005 May;128(5):1437-44
pubmed: 15887125
Hepatology. 2014 Apr;59(4):1262-72
pubmed: 23929627
N Engl J Med. 1976 Sep 2;295(10):517-22
pubmed: 950957
Front Physiol. 2011 Feb 24;2:4
pubmed: 21483730
Cancer Chemother Pharmacol. 2011 Mar;67(3):657-66
pubmed: 20509027
Nat Rev Immunol. 2004 Jun;4(6):445-56
pubmed: 15173833
Exp Mol Med. 2018 Mar 2;50(3):e453
pubmed: 29497170
Gastroenterology. 2010 Mar;138(3):1123-33.e1-3
pubmed: 19900446
Nat Rev Immunol. 2014 Jan;14(1):36-49
pubmed: 24362405
N Engl J Med. 2006 Dec 7;355(23):2444-51
pubmed: 17151366
CPT Pharmacometrics Syst Pharmacol. 2017 Feb;6(2):136-146
pubmed: 28130915
Antimicrob Agents Chemother. 2010 Mar;54(3):1179-85
pubmed: 20028817
J Mol Biol. 2004 Jul 30;341(1):303-18
pubmed: 15312780
N Engl J Med. 2008 Dec 4;359(23):2429-41
pubmed: 19052125
Dig Dis Sci. 1998 Jul;43(7):1562-5
pubmed: 9690395
Eur J Clin Pharmacol. 1985;28(4):469-71
pubmed: 4029251
Arch Virol. 1981;68(1):19-25
pubmed: 6166278
Clin Microbiol Rev. 2001 Oct;14(4):778-809, table of contents
pubmed: 11585785
Clin Pharmacol Ther. 1984 May;35(5):722-7
pubmed: 6713784
Bioinformatics. 2006 Dec 15;22(24):3067-74
pubmed: 17032683
Lancet. 1998 Jan 31;351(9099):351-5
pubmed: 9652633
J Physiol. 2017 Dec 15;595(24):7311-7330
pubmed: 28960303
N Engl J Med. 2011 Jun 23;364(25):2405-16
pubmed: 21696307
J Pharmacokinet Pharmacodyn. 2018 Apr;45(2):235-257
pubmed: 29234936
Biophys J. 2006 May 1;90(9):3345-55
pubmed: 16473899
J Biol Chem. 2002 Dec 20;277(51):49428-37
pubmed: 12386168
J Interferon Cytokine Res. 2002 Dec;22(12):1185-9
pubmed: 12581491
J Clin Oncol. 1984 Mar;2(3):221-6
pubmed: 6321691
Regul Pept. 2012 Jan 10;173(1-3):74-81
pubmed: 21985916
NPJ Syst Biol Appl. 2018 Feb 26;4:10
pubmed: 29507756
World J Gastroenterol. 2012 Oct 21;18(39):5514-20
pubmed: 23112543
Arch Toxicol. 2017 Feb;91(2):865-883
pubmed: 27161439
JAKSTAT. 2013 Oct 1;2(4):e25530
pubmed: 24416649
N Engl J Med. 1992 Dec 31;327(27):1899-905
pubmed: 1280771
FEBS J. 2010 Nov;277(22):4741-54
pubmed: 20964804
Immunity. 2012 Apr 20;36(4):503-14
pubmed: 22520844
Biologics. 2008 Dec;2(4):635-43
pubmed: 19707444
Semin Liver Dis. 2004;24 Suppl 2:33-8
pubmed: 15346244
J Pharmacol Exp Ther. 2003 Jul;306(1):262-70
pubmed: 12660309
N Engl J Med. 2011 Mar 31;364(13):1195-206
pubmed: 21449783
Pharm Res. 2002 Oct;19(10):1537-43
pubmed: 12425473
Br J Clin Pharmacol. 1999 Apr;47(4):365-71
pubmed: 10233199
Clin Pharmacol Ther. 1996 Jun;59(6):636-46
pubmed: 8681488
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
pubmed: 18467494
PLoS Comput Biol. 2012;8(10):e1002750
pubmed: 23133351
Am J Hematol. 1984;17(4):363-71
pubmed: 6594039
Eur J Pharm Sci. 2016 Oct 30;94:4-14
pubmed: 27131606
J Interferon Res. 1986 Jun;6(3):207-13
pubmed: 3745986
NPJ Syst Biol Appl. 2018 Aug 3;4:28
pubmed: 30083389
JAKSTAT. 2013 Jul 1;2(3):e24672
pubmed: 24069559
Liver Int. 2009 Jan;29 Suppl 1:74-81
pubmed: 19207969
Drug Metab Dispos. 2012 May;40(5):892-901
pubmed: 22293118
Sci Rep. 2016 Aug 22;6:31349
pubmed: 27546197
J Clin Pharmacol. 1987 May-Jun;27(5):432-5
pubmed: 3693589
N Engl J Med. 2002 Sep 26;347(13):975-82
pubmed: 12324553
Mol Syst Biol. 2012 May 22;8:584
pubmed: 22617958
Nat Biotechnol. 2007 Sep;25(9):1001-6
pubmed: 17846631
Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1198-205
pubmed: 8108387
Bioinformatics. 2003 Mar 1;19(4):524-31
pubmed: 12611808
Prog Biophys Mol Biol. 2011 Aug;106(2):426-34
pubmed: 21762720
Biophys J. 2005 Jun;88(6):4289-302
pubmed: 15778442
Pharm Res. 2010 May;27(5):920-32
pubmed: 20232116
Hepatology. 2014 Apr;59(4):1250-61
pubmed: 23913866
FEBS Lett. 2003 Jan 16;534(1-3):190-6
pubmed: 12527385
Arch Toxicol. 2018 Jan;92(1):553-555
pubmed: 28852801
PLoS Comput Biol. 2017 Feb 2;13(2):e1005280
pubmed: 28151932
CPT Pharmacometrics Syst Pharmacol. 2016 Oct;5(10):516-531
pubmed: 27653238
Cancer Res. 1990 Aug 1;50(15):4718-23
pubmed: 2369745