Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis. Gausi, K., Chirehwa, M., Ignatius, E. H, Court, R., Sun, X., Moran, L., Hafner, R., Wiesner, L., Rosenkranz, S. L, de Jager, V., de Vries, N., Harding, J., Gumbo, T., Swindells, S., Diacon, A., Dooley, K. E, McIlleron, H., & Denti, P. Journal of Antimicrobial Chemotherapy, 77(9):2489–2499, Oxford Academic, aug, 2022. ![Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharma-cokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. Objectives: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. Methods: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransfer-ase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. Conclusions: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses .10 mg/kg. The safety implications of these phenomena remain unclear.
@article{Gausi2022,
abstract = {Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharma-cokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. Objectives: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. Methods: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransfer-ase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50{\%} beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6{\%} lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29{\%} increase in isoniazid AUC. Conclusions: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses .10 mg/kg. The safety implications of these phenomena remain unclear.},
author = {Gausi, Kamunkhwala and Chirehwa, Maxwell and Ignatius, Elisa H and Court, Richard and Sun, Xin and Moran, Laura and Hafner, Richard and Wiesner, Lubbe and Rosenkranz, Susan L and de Jager, Veronique and de Vries, Nihal and Harding, Joseph and Gumbo, Tawanda and Swindells, Susan and Diacon, Andreas and Dooley, Kelly E and McIlleron, Helen and Denti, Paolo},
doi = {10.1093/JAC/DKAC188},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gausi et al. - 2022 - Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {aug},
number = {9},
pages = {2489--2499},
pmid = {35678468},
publisher = {Oxford Academic},
title = {{Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis}},
url = {https://academic.oup.com/jac/article/77/9/2489/6604654},
volume = {77},
year = {2022}
}
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Methods: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransfer-ase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. Conclusions: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses .10 mg/kg. The safety implications of these phenomena remain unclear.","author":[{"propositions":[],"lastnames":["Gausi"],"firstnames":["Kamunkhwala"],"suffixes":[]},{"propositions":[],"lastnames":["Chirehwa"],"firstnames":["Maxwell"],"suffixes":[]},{"propositions":[],"lastnames":["Ignatius"],"firstnames":["Elisa","H"],"suffixes":[]},{"propositions":[],"lastnames":["Court"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["Sun"],"firstnames":["Xin"],"suffixes":[]},{"propositions":[],"lastnames":["Moran"],"firstnames":["Laura"],"suffixes":[]},{"propositions":[],"lastnames":["Hafner"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["Wiesner"],"firstnames":["Lubbe"],"suffixes":[]},{"propositions":[],"lastnames":["Rosenkranz"],"firstnames":["Susan","L"],"suffixes":[]},{"propositions":["de"],"lastnames":["Jager"],"firstnames":["Veronique"],"suffixes":[]},{"propositions":["de"],"lastnames":["Vries"],"firstnames":["Nihal"],"suffixes":[]},{"propositions":[],"lastnames":["Harding"],"firstnames":["Joseph"],"suffixes":[]},{"propositions":[],"lastnames":["Gumbo"],"firstnames":["Tawanda"],"suffixes":[]},{"propositions":[],"lastnames":["Swindells"],"firstnames":["Susan"],"suffixes":[]},{"propositions":[],"lastnames":["Diacon"],"firstnames":["Andreas"],"suffixes":[]},{"propositions":[],"lastnames":["Dooley"],"firstnames":["Kelly","E"],"suffixes":[]},{"propositions":[],"lastnames":["McIlleron"],"firstnames":["Helen"],"suffixes":[]},{"propositions":[],"lastnames":["Denti"],"firstnames":["Paolo"],"suffixes":[]}],"doi":"10.1093/JAC/DKAC188","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gausi et al. - 2022 - Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.pdf:pdf","issn":"0305-7453","journal":"Journal of Antimicrobial Chemotherapy","keywords":"fund_not_ack,original","mendeley-tags":"fund_not_ack,original","month":"aug","number":"9","pages":"2489–2499","pmid":"35678468","publisher":"Oxford Academic","title":"Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis","url":"https://academic.oup.com/jac/article/77/9/2489/6604654","volume":"77","year":"2022","bibtex":"@article{Gausi2022,\r\nabstract = {Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. 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