Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (C (max)), especially of rifampicin and isoniazid, are well below the proposed target C (max) concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment's success rate in these studies was typically at least 85 %. The proposed target C (max) concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C (max) based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C (max) (or area under the curve (AUC)) and C (max)/MIC (or AUC/MIC). Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.