Katarina Niward1,2, Lina Davies Forsman3,4, Judith Bruchfeld3,4, Erja Chryssanthou5,6, Oskar Carlström2, Teba Alomari2, Björn Carlsson7, Anton Pohanka8, Mikael Mansjö9, Michaela Jonsson Nordvall10, Anders G Johansson10, Erik Eliasson8, Jim Werngren9, Jakob Paues1,2, Ulrika S H Simonsson11, Thomas Schön1,12. 1. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 2. Department of Infectious Diseases, University Hospital Linköping, Linköping, Sweden. 3. Department of Medicine Solna, Unit of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden. 4. Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden. 5. Department of Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden. 6. Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 7. Department of Clinical Pharmacology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. 8. Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge, Stockholm, Sweden. 9. Department of Microbiology, Public Health Agency of Sweden, Stockholm, Sweden. 10. Department of Clinical Microbiology, University Hospital Linköping, Linköping, Sweden. 11. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 12. Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
Abstract
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 (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/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 Chigh 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 AUC0-6/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.
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 TBpatients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/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 Chigh 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 AUC0-6/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.
Authors: Robin J Svensson; Katarina Niward; Lina Davies Forsman; Judith Bruchfeld; Jakob Paues; Erik Eliasson; Thomas Schön; Ulrika S H Simonsson Journal: Br J Clin Pharmacol Date: 2019-07-25 Impact factor: 4.335
Authors: Navarat Panjasawatwong; Thanaporn Wattanakul; Richard M Hoglund; Nguyen Duc Bang; Thomas Pouplin; Wichit Nosoongnoen; Vi Nguyen Ngo; Jeremy N Day; Joel Tarning Journal: Antimicrob Agents Chemother Date: 2020-12-16 Impact factor: 5.191
Authors: David Ekqvist; Anna Bornefall; Daniel Augustinsson; Martina Sönnerbrandt; Michaela Jonsson Nordvall; Mats Fredrikson; Björn Carlsson; Mårten Sandstedt; Ulrika S H Simonsson; Jan-Willem C Alffenaar; Jakob Paues; Katarina Niward Journal: BMJ Open Date: 2022-03-10 Impact factor: 2.692