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JAC Advance Access originally published online on July 19, 2006
Journal of Antimicrobial Chemotherapy 2006 58(3):594-600; doi:10.1093/jac/dkl272
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Optimal sampling strategies for early pharmacodynamic measures in tuberculosis

G. R. Davies1,*, S. H. Khoo2 and L. J. Aarons3

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

Received 16 January 2006; returned 16 March 2006; revised 5 May 2006; accepted 1 June 2006

*Corresponding author. Tel: +44-151-7944221; Fax: +44-151-7944222; E-mail: gdavies{at}doctors.org.uk

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


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