PMID- 28000286
OWN - NLM
STAT- MEDLINE
DCOM- 20180122
LR  - 20211204
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 83
IP  - 5
DP  - 2017 May
TI  - Population pharmacokinetics of temsirolimus and sirolimus in children with 
      recurrent solid tumours: a report from the Children's Oncology Group.
PG  - 1097-1107
LID - 10.1111/bcp.13181 [doi]
AB  - AIMS: Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). 
      Pharmacokinetic (PK) characterization of temsirolimus in children is limited and 
      there is no paediatric temsirolimus population PK model available. The objective 
      of this study was to simultaneously characterize the PK of temsirolimus and its 
      metabolite sirolimus in paediatric patients with recurrent solid or central 
      nervous system tumours and to develop a population PK model. METHODS: The PK data 
      for temsirolimus and sirolimus were collected as a part of a Children's Oncology 
      Group phase I clinical trial in paediatric patients with recurrent solid tumours. 
      Serial blood concentrations obtained from 19 patients participating in the PK 
      portion of the study were used for the analysis. Population PK analysis was 
      performed by nonlinear mixed effect modelling using NONMEM. RESULTS: A 
      three-compartment model with zero-order infusion was found to best describe 
      temsirolimus PK. Allometrically scaled body weight was included in the model to 
      account for body size differences. Temsirolimus dose was identified as a 
      significant covariate on clearance. A sirolimus metabolite formation model was 
      developed and integrated with the temsirolimus model. A two-compartment structure 
      model adequately described the sirolimus data. CONCLUSION: This study is the 
      first to describe a population PK model of temsirolimus combined with sirolimus 
      formation and disposition in paediatric patients. The developed model will 
      facilitate PK model-based dose individualization of temsirolimus and the design 
      of future clinical studies in children.
CI  - (c) 2016 The British Pharmacological Society.
FAU - Mizuno, Tomoyuki
AU  - Mizuno T
AD  - Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, Ohio, USA.
FAU - Fukuda, Tsuyoshi
AU  - Fukuda T
AD  - Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, Ohio, USA.
AD  - Department of Pediatrics, College of Medicine, University of Cincinnati, 
      Cincinnati, Ohio, USA.
FAU - Christians, Uwe
AU  - Christians U
AD  - iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado, 
      USA.
FAU - Perentesis, John P
AU  - Perentesis JP
AD  - Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's 
      Hospital Medical Center, Cincinnati, Ohio, USA.
AD  - Department of Pediatrics, College of Medicine, University of Cincinnati, 
      Cincinnati, Ohio, USA.
FAU - Fouladi, Maryam
AU  - Fouladi M
AD  - Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's 
      Hospital Medical Center, Cincinnati, Ohio, USA.
AD  - Department of Pediatrics, College of Medicine, University of Cincinnati, 
      Cincinnati, Ohio, USA.
FAU - Vinks, Alexander A
AU  - Vinks AA
AD  - Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, Ohio, USA.
AD  - Department of Pediatrics, College of Medicine, University of Cincinnati, 
      Cincinnati, Ohio, USA.
LA  - eng
GR  - UM1 CA097452/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20161220
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antineoplastic Agents)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adolescent
MH  - Antineoplastic Agents/administration & dosage/*pharmacokinetics
MH  - Child
MH  - Child, Preschool
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Infant
MH  - Male
MH  - *Models, Biological
MH  - Neoplasm Recurrence, Local
MH  - Neoplasms/*drug therapy/pathology
MH  - Nonlinear Dynamics
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Young Adult
PMC - PMC5401981
OTO - NOTNLM
OT  - mTOR inhibitor
OT  - paediatrics
OT  - population pharmacokinetics
OT  - sirolimus
OT  - temsirolimus
EDAT- 2016/12/22 06:00
MHDA- 2018/01/23 06:00
PMCR- 2018/05/01
CRDT- 2016/12/22 06:00
PHST- 2016/06/25 00:00 [received]
PHST- 2016/10/20 00:00 [revised]
PHST- 2016/11/01 00:00 [accepted]
PHST- 2016/12/22 06:00 [pubmed]
PHST- 2018/01/23 06:00 [medline]
PHST- 2016/12/22 06:00 [entrez]
PHST- 2018/05/01 00:00 [pmc-release]
AID - BCP13181 [pii]
AID - 10.1111/bcp.13181 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2017 May;83(5):1097-1107. doi: 10.1111/bcp.13181. Epub 2016 
      Dec 20.