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2018 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 10, p. 2838-2845Article in journal (Refereed) Published
Abstract [en]
Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-153707 (URN)10.1093/jac/dky268 (DOI)000452914200032 ()30124844 (PubMedID)
Note
Funding Agencies|Research Council of Southeast Sweden; Region of Ostergotland; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Stockholm County Council [ALF20160331]
2019-01-072019-01-072019-05-02