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Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Univ Hosp Linkoping, Dept Infect Dis, S-58185 Linkoping, Sweden.
Karolinska Inst, Dept Med Solna, Unit Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden.
Karolinska Inst, Dept Med Solna, Unit Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden.
Karolinska Univ Hosp Solna, Dept Clin Microbiol, Stockholm, Sweden;Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
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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 (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<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. Vol. 73, no 10, p. 2838-2845
National Category
Pharmacology and Toxicology
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URN: urn:nbn:se:uu:diva-372900DOI: 10.1093/jac/dky268ISI: 000452914200032PubMedID: 30124844OAI: oai:DiVA.org:uu-372900DiVA, id: diva2:1278354
Funder
Swedish Research CouncilMedical Research Council of Southeast Sweden (FORSS)Marianne and Marcus Wallenberg FoundationSwedish Heart Lung FoundationStockholm County CouncilAvailable from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved

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Simonsson, Ulrika S H

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