Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis

Antonia Morita I Saktiawati, Marcel Harkema, Althaf Setyawan, Yanri W Subronto, [No Value] Sumardi, Ymkje Stienstra, Rob E Aarnoutse, Cecile Magis-Escurra, Jos G W Kosterink, Tjip S van der Werf, Jan-Willem C Alffenaar, Marieke G G Sturkenboom

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BACKGROUND: The 24-h area under the concentration-time curve (AUC24)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC24; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs.

METHODS: An OSS for the prediction of AUC24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment.

RESULTS: OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS2-4-8 cannot be used for rifampicin in steady state conditions.

CONCLUSION: OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC24 values of first-line anti-TB drugs in this population.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT02121314).

Original languageEnglish
Pages (from-to)1445-1454
Number of pages10
JournalClinical Pharmacokinetics
Issue number11
Early online date10-May-2019
Publication statusPublished - Nov-2019


  • adult
  • article
  • controlled study
  • crossover procedure
  • drug monitoring
  • drug therapy
  • ethnicity
  • fasting
  • female
  • human
  • human tissue
  • jackknife test
  • male
  • multiple linear regression analysis
  • prediction
  • prospective study
  • randomized controlled trial
  • registration
  • sampling
  • steady state
  • tuberculosis
  • validation process
  • ethambutol
  • isoniazid
  • pyrazinamide
  • rifampicin

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