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

Roger K. Verbeeck, Gunar Günther, Dan Kibuule, Christian Hunter, Tim W. Rennie

Research output: Contribution to journalReview articlepeer-review

48 Citations (SciVal)

Abstract

Introduction: Tuberculosis (TB) remains one of the world’s deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95–98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. Methods: 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 (Cmax), especially of rifampicin and isoniazid, are well below the proposed target Cmax 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 %. Discussion: The proposed target Cmax concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of Cmax 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, Cmax (or area under the curve (AUC)) and Cmax/MIC (or AUC/MIC). Conclusion: 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.

Original languageEnglish
Pages (from-to)905-916
Number of pages12
JournalEuropean Journal of Clinical Pharmacology
Volume72
Issue number8
DOIs
Publication statusPublished - 1 Aug 2016

Keywords

  • Anti-TB drugs
  • Ethambutol
  • Isoniazid
  • Pyrazinamide
  • Rifampicin
  • Therapeutic drug monitoring

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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