PMID- 31671257
OWN - NLM
STAT- MEDLINE
DCOM- 20200826
LR  - 20211204
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 8
IP  - 12
DP  - 2019 Dec
TI  - A Citrulline-Based Translational Population System Toxicology Model for 
      Gastrointestinal-Related Adverse Events Associated With Anticancer Treatments.
PG  - 951-961
LID - 10.1002/psp4.12475 [doi]
AB  - Gastrointestinal (GI)-related adverse events (AEs) are commonly observed in the 
      clinic during cancer treatments. Citrulline is a potentially translatable 
      biomarker of GI AEs. In this study, irinotecan-induced citrulline changes were 
      studied for a range of doses and schedules in rats. A translational system 
      toxicology model for GI AEs using citrulline was then developed based on new 
      experimental data and parameters from a literature intestinal cell dynamic model. 
      With the addition of feedback-development and tolerance-development mechanisms, 
      the model well captured the plasma citrulline profiles after irinotecan treatment 
      in rats. Subsequently, the model was translated to humans and predicted the 
      observed GI AE dynamics in humans including dose-scheduling effect using the 
      cytotoxic and feedback parameters estimated in rats with slight calibrations. 
      This translational toxicology model could be used for other antineoplastic drugs 
      to simulate various clinical dosing scenarios before human studies and mitigate 
      potential GI AEs.
CI  - (c) 2019 Takeda Pharmaceuticals, Co. CPT: Pharmacometrics & Systems Pharmacology 
      published by Wiley Periodicals, Inc. on behalf of the American Society for 
      Clinical Pharmacology and Therapeutics.
FAU - Yoneyama, Tomoki
AU  - Yoneyama T
AUID- ORCID: 0000-0002-2207-3505
AD  - Quantitative Translational Sciences, Takeda Pharmaceuticals International Co., 
      Cambridge, Massachusetts, USA.
FAU - Abdul-Hadi, Kojo
AU  - Abdul-Hadi K
AD  - Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International 
      Co., Cambridge, Massachusetts, USA.
FAU - Brown, Adam
AU  - Brown A
AD  - Global Drug Safety Research and Evaluation, Takeda Pharmaceuticals International 
      Co., Cambridge, Massachusetts, USA.
FAU - Guan, Emily
AU  - Guan E
AD  - Global Drug Safety Research and Evaluation, Takeda Pharmaceuticals International 
      Co., Cambridge, Massachusetts, USA.
FAU - Wagoner, Matt
AU  - Wagoner M
AD  - Global Drug Safety Research and Evaluation, Takeda Pharmaceuticals International 
      Co., Cambridge, Massachusetts, USA.
FAU - Zhu, Andy Z X
AU  - Zhu AZX
AD  - Quantitative Translational Sciences, Takeda Pharmaceuticals International Co., 
      Cambridge, Massachusetts, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191112
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - 0 (Antineoplastic Agents)
RN  - 29VT07BGDA (Citrulline)
RN  - 7673326042 (Irinotecan)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*toxicity
MH  - Citrulline/*blood
MH  - Disease Models, Animal
MH  - Gastrointestinal Tract/drug effects/*metabolism
MH  - Humans
MH  - Irinotecan/administration & dosage/*toxicity
MH  - Rats
MH  - Toxicity Tests
MH  - Translational Research, Biomedical
PMC - PMC6930863
COIS- The authors are employed by Takeda Pharmaceuticals International Co. The authors 
      declare no additional conflict of interest.
EDAT- 2019/11/02 06:00
MHDA- 2020/08/28 06:00
PMCR- 2019/12/01
CRDT- 2019/11/01 06:00
PHST- 2019/06/14 00:00 [received]
PHST- 2019/09/02 00:00 [accepted]
PHST- 2019/11/02 06:00 [pubmed]
PHST- 2020/08/28 06:00 [medline]
PHST- 2019/11/01 06:00 [entrez]
PHST- 2019/12/01 00:00 [pmc-release]
AID - PSP412475 [pii]
AID - 10.1002/psp4.12475 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2019 Dec;8(12):951-961. doi: 
      10.1002/psp4.12475. Epub 2019 Nov 12.