Journal of Antimicrobial Chemotherapy Advance Access published September 22, 2014
J Antimicrob Chemother doi:10.1093/jac/dku373
Clinical significance of 2 h plasma concentrations of first-line antituberculosis drugs: a prospective observational study—authors’ response
1
International Reference Laboratory of Mycobacteriology, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark; 2 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; 3Department of Biochemistry, Immunology and Genetics, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark; 4Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Kettega˚rd Alle 30, 2650 Hvidovre, Denmark; 5Department of Infectious Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen Ø, Denmark *Corresponding author. E-mail: [email protected]
Keywords: anti-tuberculosis drugs, tuberculosis, therapeutic drug
monitoring Sir, We thank Pasipanodya et al.1 for their interest in our study.2 The study was the first in a series of clinical studies measuring all four anti-TB drugs (rifampicin, isoniazid, ethambutol and pyrazinamide) simultaneously in blood samples from TB patients after developing an LC-MS/MS method at Statens Serum Institut, Copenhagen, Denmark. Until then samples were shipped overseas for analysis, which naturally took some time. Now plasma drug concentrations can be determined and reported the same day. In Denmark TB patients are managed at a relatively few centres by infectious disease or pulmonary medicine specialists. There has until now not been consensus on when and why the plasma concentrations of anti-TB drugs should be monitored. The currently used 2 h blood sampling strategy and the use of normal Cmax concentrations from healthy adults as normal 2 h values are based on studies of Peloquin.3 Due to the relatively scarce and somewhat confusing published data on the pharmacokinetics and pharmacodynamics of standard anti-TB drugs, we have also performed more detailed pharmacokinetic analyses of all four compounds at 1 week and 4 weeks after the initiation of treatment of TB and will correlate these with the treatment effects including Monte Carlo simulation in order to estimate the optimal doses of rifampicin and isoniazid (J. B. Prahl, K. Skovbo Jensen, N. Seersholm, T. Wilcke, A˚. B. Andersen, A. S. Cohen and N. Frimodt-Møller, unpublished data). Even though the sample size in our study2 is small, the 18% failure rate corresponds to the overall failure rate in Denmark.4
Transparency declarations None to declare.
References 1 Pasipanodya JG, Srivastava S, Gumbo T. Comment on: Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother 2014; doi:10.1093/jac/dku345. 2 Prahl JB, Johansen IS, Cohen AS et al. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother 2014; 69: 2841 –7. 3 Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002; 62: 2169– 83. 4 Lillebaek T, Poulsen S, Kok-Jensen A. Tuberculosis treatment in Denmark: treatment outcome for all Danish patients in 1992. Int J Tuberc Lung Dis 1999; 3: 603–12. 5 Pasipanodya JG, McIlleron H, Burger A et al. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis 2013; 208: 1464– 73.
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
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Julie B. Prahl1*, Isik S. Johansen2, Arieh S. Cohen3, Niels Frimodt-Møller4 and A˚se B. Andersen5
We fully agree on the problem of taking only a 2 h blood sample as a marker for peak drug concentrations and further explore this issue in the above-mentioned pharmacokinetic study of the four anti-TB drugs. Nevertheless, it is noteworthy that the CRP level at the time of sampling correlates inversely with the 2 h plasma concentration of isoniazid and that therapy failure occurs more frequently in patients with lower 2 h plasma concentration levels of isoniazid and/or rifampicin. However, in order to perform more relevant pharmacokinetic/pharmacodynamic analysis, e.g. estimates of AUC/MIC ratios, we recommend that at least two blood samples, drawn at 1 h and at 3–4 h after drug intake, should be analysed. Only one patient was excluded from our study2 due to a suspicion of poor adherence to treatment. As no follow-up was performed, this patient could not contribute to the interesting discussion regarding the effect on treatment outcome of pharmacokinetic variability versus non-adherence. We did not experience the development of resistance in any of the cases of TB, although control sputum samples for the culture of Mycobacterium tuberculosis were only available for those patients with persistent expectoration. Also, no association could be demonstrated between 2 month sputum conversion and plasma concentrations above or below the previously suggested5 concentration thresholds for rifampicin, isoniazid or pyrazinamide. We think that our study2 together with recent studies, not the least from Professor Gumbo and coworkers, calls for standard, routine therapeutic drug monitoring for all TB patients in Denmark; when embarking on a 6 month treatment of a deadly disease, it should be imperative—if the means and methods are available—to monitor whether the doses are correct. However, we still need further evidence on what drug concentrations are necessary, especially in combination treatment, as well as data on the relationships between drug concentrations and adverse effects.
J Antimicrob Chemother doi:10.1093/jac/dku373
Clinical significance of 2 h plasma concentrations of first-line antituberculosis drugs: a prospective observational study—authors’ response
1
International Reference Laboratory of Mycobacteriology, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark; 2 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; 3Department of Biochemistry, Immunology and Genetics, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark; 4Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Kettega˚rd Alle 30, 2650 Hvidovre, Denmark; 5Department of Infectious Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen Ø, Denmark *Corresponding author. E-mail: [email protected]
Keywords: anti-tuberculosis drugs, tuberculosis, therapeutic drug
monitoring Sir, We thank Pasipanodya et al.1 for their interest in our study.2 The study was the first in a series of clinical studies measuring all four anti-TB drugs (rifampicin, isoniazid, ethambutol and pyrazinamide) simultaneously in blood samples from TB patients after developing an LC-MS/MS method at Statens Serum Institut, Copenhagen, Denmark. Until then samples were shipped overseas for analysis, which naturally took some time. Now plasma drug concentrations can be determined and reported the same day. In Denmark TB patients are managed at a relatively few centres by infectious disease or pulmonary medicine specialists. There has until now not been consensus on when and why the plasma concentrations of anti-TB drugs should be monitored. The currently used 2 h blood sampling strategy and the use of normal Cmax concentrations from healthy adults as normal 2 h values are based on studies of Peloquin.3 Due to the relatively scarce and somewhat confusing published data on the pharmacokinetics and pharmacodynamics of standard anti-TB drugs, we have also performed more detailed pharmacokinetic analyses of all four compounds at 1 week and 4 weeks after the initiation of treatment of TB and will correlate these with the treatment effects including Monte Carlo simulation in order to estimate the optimal doses of rifampicin and isoniazid (J. B. Prahl, K. Skovbo Jensen, N. Seersholm, T. Wilcke, A˚. B. Andersen, A. S. Cohen and N. Frimodt-Møller, unpublished data). Even though the sample size in our study2 is small, the 18% failure rate corresponds to the overall failure rate in Denmark.4
Transparency declarations None to declare.
References 1 Pasipanodya JG, Srivastava S, Gumbo T. Comment on: Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother 2014; doi:10.1093/jac/dku345. 2 Prahl JB, Johansen IS, Cohen AS et al. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother 2014; 69: 2841 –7. 3 Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002; 62: 2169– 83. 4 Lillebaek T, Poulsen S, Kok-Jensen A. Tuberculosis treatment in Denmark: treatment outcome for all Danish patients in 1992. Int J Tuberc Lung Dis 1999; 3: 603–12. 5 Pasipanodya JG, McIlleron H, Burger A et al. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis 2013; 208: 1464– 73.
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 1
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 4, 2014
Julie B. Prahl1*, Isik S. Johansen2, Arieh S. Cohen3, Niels Frimodt-Møller4 and A˚se B. Andersen5
We fully agree on the problem of taking only a 2 h blood sample as a marker for peak drug concentrations and further explore this issue in the above-mentioned pharmacokinetic study of the four anti-TB drugs. Nevertheless, it is noteworthy that the CRP level at the time of sampling correlates inversely with the 2 h plasma concentration of isoniazid and that therapy failure occurs more frequently in patients with lower 2 h plasma concentration levels of isoniazid and/or rifampicin. However, in order to perform more relevant pharmacokinetic/pharmacodynamic analysis, e.g. estimates of AUC/MIC ratios, we recommend that at least two blood samples, drawn at 1 h and at 3–4 h after drug intake, should be analysed. Only one patient was excluded from our study2 due to a suspicion of poor adherence to treatment. As no follow-up was performed, this patient could not contribute to the interesting discussion regarding the effect on treatment outcome of pharmacokinetic variability versus non-adherence. We did not experience the development of resistance in any of the cases of TB, although control sputum samples for the culture of Mycobacterium tuberculosis were only available for those patients with persistent expectoration. Also, no association could be demonstrated between 2 month sputum conversion and plasma concentrations above or below the previously suggested5 concentration thresholds for rifampicin, isoniazid or pyrazinamide. We think that our study2 together with recent studies, not the least from Professor Gumbo and coworkers, calls for standard, routine therapeutic drug monitoring for all TB patients in Denmark; when embarking on a 6 month treatment of a deadly disease, it should be imperative—if the means and methods are available—to monitor whether the doses are correct. However, we still need further evidence on what drug concentrations are necessary, especially in combination treatment, as well as data on the relationships between drug concentrations and adverse effects.
