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Use of Nonlinear Mixed-Effects Analysis for Improved Precision of Early Pharmacodynamic Measures in Tuberculosis Treatment

Wellcome Trust Centre for Clinical Tropical Medicine, University of Liverpool, Liverpool, United Kingdom,¹ Department of Clinical Microbiology, Portsmouth Hospitals, Portsmouth, United Kingdom,² Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom,³ School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom⁴

Received 20 June 2005/ Returned for modification 7 March 2006/ Accepted 12 June 2006

Nonlinear mixed-effects analysis of serial sputum colony-counting data supports the existence of two bacillary subpopulations in sputum, eliminated at different rates. It distinguishes between combination regimens, removes bias, and greatly improves precision, with significant implications for the analysis of surrogate endpoints of "sterilization" in the development of new antituberculosis regimens.