PMID- 28129975
OWN - NLM
STAT- MEDLINE
DCOM- 20170818
LR  - 20181202
IS  - 1880-0920 (Electronic)
IS  - 1347-4367 (Linking)
VI  - 32
IP  - 1
DP  - 2017 Feb
TI  - The role of quantitative systems pharmacology modeling in the prediction and 
      explanation of idiosyncratic drug-induced liver injury.
PG  - 40-45
LID - S1347-4367(16)30055-6 [pii]
LID - 10.1016/j.dmpk.2016.11.008 [doi]
AB  - Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug 
      development. The rarity and multifactorial nature of iDILI makes it difficult to 
      predict and explain. Recently, human leukocyte antigen (HLA) allele associations 
      have provided strong support for a role of an adaptive immune response in the 
      pathogenesis of many iDILI cases; however, it is likely that an adaptive immune 
      attack requires several preceding events. Quantitative systems pharmacology 
      (QSP), an in silico modeling technique that leverages known physiology and the 
      results of in vitro experiments in order to make predictions about how drugs 
      affect biological processes, is proposed as a potentially useful tool for 
      predicting and explaining critical events that likely precede immune-mediated 
      iDILI, as well as the immune attack itself. DILIsym, a QSP platform for 
      drug-induced liver injury, has demonstrated success in predicting the presence of 
      delayed hepatocellular stress events that likely precede the iDILI cascade, and 
      has successfully predicted hepatocellular stress likely underlying iDILI 
      attributed to troglitazone and tolvaptan. The incorporation of a model of the 
      adaptive immune system into DILIsym would represent and important advance. In 
      summary, QSP methods can play a key role in the future prediction and 
      understanding of both immune-mediated and non-immune-mediated iDILI.
CI  - Copyright (c) 2016 The Japanese Society for the Study of Xenobiotics. Published by 
      Elsevier Ltd. All rights reserved.
FAU - Woodhead, Jeffrey L
AU  - Woodhead JL
AD  - DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA. 
      Electronic address: jwoodhead@dilisym.com.
FAU - Watkins, Paul B
AU  - Watkins PB
AD  - Institute for Drug Safety Sciences, UNC-Eshelman School of Pharmacy, 6 Davis 
      Drive, Research Triangle Park, NC 27709, USA.
FAU - Howell, Brett A
AU  - Howell BA
AD  - DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
FAU - Siler, Scott Q
AU  - Siler SQ
AD  - DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
FAU - Shoda, Lisl K M
AU  - Shoda LKM
AD  - DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20161121
PL  - England
TA  - Drug Metab Pharmacokinet
JT  - Drug metabolism and pharmacokinetics
JID - 101164773
RN  - 0 (Benzazepines)
RN  - 0 (Chromans)
RN  - 0 (Thiazolidinediones)
RN  - 21G72T1950 (Tolvaptan)
RN  - I66ZZ0ZN0E (Troglitazone)
SB  - IM
MH  - Animals
MH  - Benzazepines/*adverse effects/immunology/therapeutic use
MH  - Chemical and Drug Induced Liver Injury/*etiology/immunology
MH  - Chromans/*adverse effects/immunology/therapeutic use
MH  - *Drug-Related Side Effects and Adverse Reactions
MH  - Humans
MH  - *Models, Biological
MH  - Thiazolidinediones/*adverse effects/immunology/therapeutic use
MH  - Tolvaptan
MH  - Troglitazone
OTO - NOTNLM
OT  - Adaptive immune system
OT  - Computer modeling
OT  - Idiosyncratic DILI
OT  - Liver injury
OT  - Quantitative systems pharmacology
EDAT- 2017/01/29 06:00
MHDA- 2017/08/19 06:00
CRDT- 2017/01/29 06:00
PHST- 2016/08/17 00:00 [received]
PHST- 2016/10/14 00:00 [revised]
PHST- 2016/11/15 00:00 [accepted]
PHST- 2017/01/29 06:00 [pubmed]
PHST- 2017/08/19 06:00 [medline]
PHST- 2017/01/29 06:00 [entrez]
AID - S1347-4367(16)30055-6 [pii]
AID - 10.1016/j.dmpk.2016.11.008 [doi]
PST - ppublish
SO  - Drug Metab Pharmacokinet. 2017 Feb;32(1):40-45. doi: 10.1016/j.dmpk.2016.11.008. 
      Epub 2016 Nov 21.