Reply to "Adequate design of pharmacokinetic-pharmacodynamic studies will help optimize tuberculosis treatment for the future"

Abstract

We thank Sturkenboom et al. for their interest in our study and their comments. The pragmatic study design based on two sampling points, 2 and 6 h after drug intake, reflected the real-world approach taken in this study, sampling patients attending a government clinic rather than in the controlled setting of a pharmacokinetic study suite. This sampling strategy has frequently been used in the past, and there are data to suggest that the peak serum concentration (Cmax) occurs between 1 and 2 h postdose when isoniazid is given on an empty stomach. If only isoniazid is being measured, a two-sample strategy with estimation of 1- and 4-h concentrations may effectively capture both the Cmax and the majority of delayed absorption. However, isoniazid is usually administered with other drugs which are somewhat more slowly absorbed (e.g., rifampin). In such cases, a 2- and 6-h-postdose sampling strategy facilitating study of both agents seems reasonable. In our study, the objective was to determine the pharmacokinetics of isoniazid and also rifampin, and thus the C2-C6 sampling strategy was chosen. Although a more intensive pharmacokinetic sampling would better capture the true Cmax values, as suggested by the authors, the logistical demands of this approach would have compromised study recruitment in most of our community clinic field sites, rendering the study unfeasible...