PMID- 28941225
OWN - NLM
STAT- MEDLINE
DCOM- 20190313
LR  - 20211204
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 7
IP  - 1
DP  - 2018 Jan
TI  - Systems Pharmacology Model of Gastrointestinal Damage Predicts Species 
      Differences and Optimizes Clinical Dosing Schedules.
PG  - 26-33
LID - 10.1002/psp4.12255 [doi]
AB  - Gastrointestinal (GI) adverse events (AEs) are frequently dose limiting for 
      oncology agents, requiring extensive clinical testing of alternative schedules to 
      identify optimal dosing regimens. Here, we develop a translational mathematical 
      model to predict these clinical AEs starting from preclinical GI toxicity data. 
      The model structure incorporates known biology and includes stem cells, daughter 
      cells, and enterocytes. Published data, including cellular numbers and division 
      times, informed the system parameters for humans and rats. The drug-specific 
      parameters were informed with preclinical histopathology data from rats treated 
      with irinotecan. The model fit the rodent irinotecan-induced pathology changes 
      well. The predicted time course of enterocyte loss in patients treated with 
      weekly doses matched observed AE profiles. The model also correctly predicts a 
      lower level of AEs for every 3 weeks (Q3W), as compared to the weekly schedule.
CI  - (c) 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley 
      Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Shankaran, Harish
AU  - Shankaran H
AD  - Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, 
      Massachusetts, USA.
FAU - Cronin, Anna
AU  - Cronin A
AD  - Drug Safety and Metabolism, IMED Biotech Unity, AstraZeneca, Cambridge, UK.
FAU - Barnes, Jen
AU  - Barnes J
AD  - Drug Safety and Metabolism, IMED Biotech Unity, AstraZeneca, Cambridge, UK.
FAU - Sharma, Pradeep
AU  - Sharma P
AD  - Drug Safety and Metabolism, IMED Biotech Unity, AstraZeneca, Cambridge, UK.
FAU - Tolsma, John
AU  - Tolsma J
AD  - RES Group, Cambridge, Massachusetts, USA.
FAU - Jasper, Paul
AU  - Jasper P
AD  - RES Group, Cambridge, Massachusetts, USA.
FAU - Mettetal, Jerome T
AU  - Mettetal JT
AD  - Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, 
      Massachusetts, USA.
LA  - eng
PT  - Journal Article
DEP - 20171206
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - 0 (Antineoplastic Agents)
RN  - 7673326042 (Irinotecan)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/toxicity
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Drug-Related Side Effects and Adverse Reactions/*etiology
MH  - Gastrointestinal Tract/*drug effects/physiology
MH  - Humans
MH  - Irinotecan/*administration & dosage/toxicity
MH  - *Models, Biological
MH  - Predictive Value of Tests
MH  - Species Specificity
MH  - Systems Biology/*methods
MH  - Translational Research, Biomedical
PMC - PMC5784737
EDAT- 2017/09/25 06:00
MHDA- 2019/03/14 06:00
PMCR- 2018/01/01
CRDT- 2017/09/24 06:00
PHST- 2017/03/24 00:00 [received]
PHST- 2017/08/08 00:00 [revised]
PHST- 2017/09/18 00:00 [accepted]
PHST- 2017/09/25 06:00 [pubmed]
PHST- 2019/03/14 06:00 [medline]
PHST- 2017/09/24 06:00 [entrez]
PHST- 2018/01/01 00:00 [pmc-release]
AID - PSP412255 [pii]
AID - 10.1002/psp4.12255 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2018 Jan;7(1):26-33. doi: 10.1002/psp4.12255. 
      Epub 2017 Dec 6.