PMID- 23400739
OWN - NLM
STAT- MEDLINE
DCOM- 20130730
LR  - 20130212
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 53
IP  - 1
DP  - 2013 Jan
TI  - Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule 
      selection for dovitinib.
PG  - 14-20
LID - 10.1177/0091270011433330 [doi]
AB  - Dovitinib is an oral multitargeted kinase inhibitor with potent activity against 
      receptors for vascular endothelial growth factor, platelet-derived growth factor, 
      and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib 
      using a continuous daily dosing schedule has shown that dovitinib exhibits a 
      prolonged and overproportional increase in dose and exposure relationship above 
      400 mg/d. To address this, intermittent dosing schedules were explored using a 
      model-based approach. A semi-mechanistic population 
      pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 
      studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) 
      responsible for dovitinib metabolism was described using an indirect response 
      model. Simulation of dovitinib plasma concentration profiles following 4 
      intermittent dosing schedules suggested that intermittent dosing could prevent 
      prolonged drug accumulation. Based on the simulated plasma profiles, PD response, 
      and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was 
      selected for a phase 1 to 2 clinical study. The observed dovitinib plasma 
      concentrations in this study confirmed the model predictions. Furthermore, 
      dovitinib was well tolerated, and antitumor activity was observed as well in this 
      new study. The 5-days-on/2-days-off dosing schedule is currently used in a 
      dovitinib registration trial and other clinical trials.
CI  - (c) 2012 The Author(s).
FAU - Wang, Xiaofeng
AU  - Wang X
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 
      Xiaofeng.wang@CSLbehring.com
FAU - Kay, Andrea
AU  - Kay A
FAU - Anak, Oezlem
AU  - Anak O
FAU - Angevin, Eric
AU  - Angevin E
FAU - Escudier, Bernard
AU  - Escudier B
FAU - Zhou, Wei
AU  - Zhou W
FAU - Feng, Yilin
AU  - Feng Y
FAU - Dugan, Margaret
AU  - Dugan M
FAU - Schran, Horst
AU  - Schran H
LA  - eng
SI  - ClinicalTrials.gov/NCT00243763
SI  - ClinicalTrials.gov/NCT00279773
SI  - ClinicalTrials.gov/NCT00303251
SI  - ClinicalTrials.gov/NCT01270906
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130124
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 
      (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one)
RN  - 0 (Benzimidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolones)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Benzimidazoles/*administration & dosage/blood/pharmacokinetics
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Models, Biological
MH  - Neoplasms/*drug therapy/metabolism
MH  - Protein Kinase Inhibitors/*administration & dosage/blood/pharmacokinetics
MH  - Quinolones/*administration & dosage/blood/pharmacokinetics
MH  - Vascular Endothelial Growth Factor A/blood
EDAT- 2013/02/13 06:00
MHDA- 2013/07/31 06:00
CRDT- 2013/02/13 06:00
PHST- 2011/06/24 00:00 [received]
PHST- 2011/11/14 00:00 [accepted]
PHST- 2013/02/13 06:00 [entrez]
PHST- 2013/02/13 06:00 [pubmed]
PHST- 2013/07/31 06:00 [medline]
AID - 10.1177/0091270011433330 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2013 Jan;53(1):14-20. doi: 10.1177/0091270011433330. Epub 2013 
      Jan 24.