Skip Navigation



JAC Advance Access published online on July 19, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl272
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
58/3/594    most recent
dkl272v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Davies, G. R.
Right arrow Articles by Aarons, L. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Davies, G. R.
Right arrow Articles by Aarons, L. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 16, 2006
Revised May 5, 2006
Accepted June 1, 2006

Original article

Optimal sampling strategies for early pharmacodynamic measures in tuberculosis

G. R. Davies 1 *, S. H. Khoo 2, and L. J. Aarons 3

1 Wellcome Trust Centre for Clinical Tropical Medicine, University of Liverpool, Merseyside, UK
2 Department of Pharmacology and Therapeutics, University of Liverpool, Merseyside, UK
3 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Lancashire, UK

* To whom correspondence should be addressed.
G. R. Davies, E-mail: gdavies{at}doctors.org.uk


  Abstract

Objectives: To evaluate whether methodological optimization of serial sputum colony counting (SSCC) studies, a potentially important component in the drug development process for tuberculosis, could significantly improve their power.

Methods: Simulations were carried out using a model derived from a large SSCC dataset. Variance inflation factors (VIFs) were calculated for model parameters, focusing on the elimination rate constant likely to reflect ‘sterilizing’ activity and sampling schemes were optimized relative to a scheme of daily sampling during the initial phase of therapy. Corresponding sample sizes required for SSCC studies using different schemes were also computed.

Results: Published sampling schemes lacked efficiency with respect to the ‘sterilizing’ phase. Pragmatic optimized schemes yielding greatest precision were achieved using eleven sampling points around a skeleton of 0, 2, 7, 14 and 56 days. The standard error of the ‘sterilizing’ rate constant was reduced more than 4-fold, and sample size for realistic treatment effects was effectively halved. Even schemes with a restricted duration of sampling to avoid high proportions of missing data and those with fewer sampling points still achieved significant gains in precision. Sensitivity analysis suggested that such schemes should continue to perform well over the immediately foreseeable range of improvements in therapy.

Conclusions: Methodological improvements in the design of SSCC studies could make them a powerful tool in Phase II development of anti-tuberculosis agents.

Keywords: tuberculosis; clinical trials; Phase II; optimal design; sample size.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.