Document Detail


Pharmacokinetics and tolerability of cediranib, a potent VEGF signalling inhibitor, in cancer patients with hepatic impairment.
MedLine Citation:
PMID:  23197081     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid tumours received a single 45 mg dose of cediranib, followed by 30 mg continuous once-daily oral dosing for 21 days after a 7-day washout period (clinicaltrials.gov identifier NCT00621725). The primary objective was to compare the single-dose pharmacokinetics (PK) of cediranib in patients with different levels of hepatic impairment classified according to the bilirubin level. Safety, tolerability, multiple-dose PK and PK stratified according to the Child-Pugh criteria were also assessed. Thirty patients received cediranib: 18 with normal-mild hepatic impairment and 12 with moderate hepatic impairment. Single-dose PK parameters were similar between the group with normal-mild hepatic impairment and the group with moderate hepatic impairment [ratio of geometric least square means: area under the curve (AUC) 1.12, 90% confidence interval (CI) 0.77-1.61; Cmax 0.95, 90% CI 0.69-1.31]. Hepatic impairment did not influence PK results in multiple dosing. After continuous once-daily dosing, the geometric least square means ratio was 0.72 (90% CI 0.51-1.03) for AUCSS and 0.67 (90% CI 0.47-0.94) for CSS,max. Similar results were obtained when patients were classified for hepatic impairment according to the Child-Pugh criteria. There was no clear difference in the incidence or the severity of adverse events between hepatic impairment groups. Moderate hepatic impairment does not appear to affect the PK profile or the tolerability of cediranib. Dose adjustments are not necessary in this patient population.
Authors:
Carla M L van Herpen; Ulrik Lassen; Ingrid M E Desar; Kathryn H Brown; Marcelo Marotti; Maja J A de Jonge
Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  24     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2012-12-14     Completed Date:  2013-05-23     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  204-11     Citation Subset:  IM    
Affiliation:
Department of Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. c.vanherpen@onco.umcn.nl
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00621725
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Area Under Curve
Female
Humans
Liver Diseases / metabolism*
Male
Middle Aged
Neoplasms / drug therapy*,  metabolism*
Quinazolines / adverse effects*,  pharmacokinetics*,  therapeutic use
Signal Transduction / drug effects
Vascular Endothelial Growth Factor A / antagonists & inhibitors*,  metabolism
Chemical
Reg. No./Substance:
0/Quinazolines; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; NQU9IPY4K9/cediranib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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