Estimating optimal therapeutic drug levels of anti-tuberculosis medications based on treatment safety and effectiveness

BackgroundTherapeutic drug ranges (TDR) for standard anti-tuberculosis (TB) treatment have been determined based on expected drug levels at least 2 hours after taking the dose. In this study we constructed TDR for TB drug levels based on minimizing drug toxicity and maximizing treatment effectiveness. MethodsParticipants were followed prospectively in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil observational cohort study. We focused on participants with culture-confirmed drug-susceptible pulmonary TB who underwent standard TB therapy. TDR were estimated for each TB drug separately: isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). TDR were defined as drug concentrations that were both safe and effective: safety was defined as the probability of having an ADR of at most 5%, while effectiveness was defined as a probability of at least 95% of not having either TB treatment failure or recurrence. ResultsThere were 765 plasma samples from 448 patients; 110 (24.6%) were people with HIV, 9 (2.0%) had a grade 3 or higher ADR, and 15 (3.3%) had treatment failure/recurrence. Higher drug concentrations of INH, RIF and EMB were associated with increased odds of having ADR. High concentrations of INH suggested protection against treatment failure/recurrence. Estimated therapeutic drug range for INH (2.3-8.2 {micro}g/ml) and for RIF (0.5-7.5 {micro}g/ml) differed from the currently recommended drug ranges (3-5 {micro}g/ml and 8-24 {micro}g/ml, respectively). Estimates for PZA and EMB were similar to the currently recommended values. ConclusionsOur estimated upper end TDR were higher for INH and lower for RIF compared to currently recommended ranges.