Document Detail

Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients.
MedLine Citation:
PMID:  14707493     Owner:  NLM     Status:  MEDLINE    
Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.
C Kloft; E-U Graefe; P Tanswell; A M Scott; R Hofheinz; A Amelsberg; M O Karlsson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Investigational new drugs     Volume:  22     ISSN:  0167-6997     ISO Abbreviation:  Invest New Drugs     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-06     Completed Date:  2004-07-19     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39-52     Citation Subset:  IM    
Freie Universitaet Berlin, Germany.
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MeSH Terms
Aged, 80 and over
Antibodies, Monoclonal / pharmacokinetics*
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Infusions, Intravenous
Metabolic Clearance Rate
Middle Aged
Models, Biological
Neoplasms / blood,  drug therapy
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/sibrotuzumab

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