Population pharmacokinetics of cycloserine, and pharmacokinetic/pharmacodynamic target attainment, in MDR-tuberculosis patients dosed with terizidone. Chirehwa, M., Court, R., De Kock, M., Wiesner, L., de Vries, N., Harding, J., Gumbo, T., Maartens, G., Warren, R., Denti, P., & McIlleron, H. Antimicrobial Agents and Chemotherapy, 64(11):e01381–20, American Society for Microbiology, aug, 2020. ![Population pharmacokinetics of cycloserine, and pharmacokinetic/pharmacodynamic target attainment, in MDR-tuberculosis patients dosed with terizidone [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis. Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine, administered as terizidone, and predict doses of terizidone attaining cycloserine exposures associated with efficacy. Plasma cycloserine was measured 2–6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. Pre-treatment MICs of cycloserine were determined on clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. Median pre-treatment MIC was 16 mg/L. A one-compartment disposition model with two clearance pathways, non-renal (0.35 L/h) and renal (0.43 L/h) described cycloserine pharmacokinetics well. Non-renal clearance and volume were allometrically scaled using fat-free mass. Smoking increased non-renal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1000 mg for patients weighing ≤ 45 kg and \textgreater 45 kg, respectively), the probability of maintaining plasma cycloserine above the MIC (T \textgreaterMIC ) for more than 30% of the dosing interval (which is associated with a 1.0 log 10 CFU/mL kill in vitro ) exceeds, 90% at MIC values ≤ 16 mg/L, but the proportion of patients achieving 100% T \textgreaterMIC (which is associated with prevention of resistance) is more than 90% only with MICs ≤ 8 mg/L. Based on a target derived in vitro , the WHO recommended doses of terizidone are effective for cycloserine MICs ≤ 8 mg/L and higher doses are required to prevent the development of resistance.
@article{Chirehwa2020,
abstract = {Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis. Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine, administered as terizidone, and predict doses of terizidone attaining cycloserine exposures associated with efficacy. Plasma cycloserine was measured 2–6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. Pre-treatment MICs of cycloserine were determined on clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. Median pre-treatment MIC was 16 mg/L. A one-compartment disposition model with two clearance pathways, non-renal (0.35 L/h) and renal (0.43 L/h) described cycloserine pharmacokinetics well. Non-renal clearance and volume were allometrically scaled using fat-free mass. Smoking increased non-renal clearance by 41{\%}. Simulations showed that with daily doses of terizidone (750 mg and 1000 mg for patients weighing ≤ 45 kg and {\textgreater} 45 kg, respectively), the probability of maintaining plasma cycloserine above the MIC (T {\textgreater}MIC ) for more than 30{\%} of the dosing interval (which is associated with a 1.0 log 10 CFU/mL kill in vitro ) exceeds, 90{\%} at MIC values ≤ 16 mg/L, but the proportion of patients achieving 100{\%} T {\textgreater}MIC (which is associated with prevention of resistance) is more than 90{\%} only with MICs ≤ 8 mg/L. Based on a target derived in vitro , the WHO recommended doses of terizidone are effective for cycloserine MICs ≤ 8 mg/L and higher doses are required to prevent the development of resistance.},
author = {Chirehwa, Maxwell and Court, Richard and {De Kock}, Mariana and Wiesner, Lubbe and de Vries, Nihal and Harding, Joseph and Gumbo, Tawanda and Maartens, Gary and Warren, Rob and Denti, Paolo and McIlleron, Helen},
doi = {10.1128/aac.01381-20},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chirehwa et al. - 2020 - Population pharmacokinetics of cycloserine, and pharmacokineticpharmacodynamic target attainment, in MDR-tuberc.pdf:pdf},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {original},
mendeley-tags = {original},
month = {aug},
number = {11},
pages = {e01381--20},
pmid = {32816738},
publisher = {American Society for Microbiology},
title = {{Population pharmacokinetics of cycloserine, and pharmacokinetic/pharmacodynamic target attainment, in MDR-tuberculosis patients dosed with terizidone}},
url = {https://aac.asm.org/content/early/2020/08/11/AAC.01381-20 https://aac.asm.org/content/early/2020/08/11/AAC.01381-20.abstract},
volume = {64},
year = {2020}
}
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Pre-treatment MICs of cycloserine were determined on clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. Median pre-treatment MIC was 16 mg/L. A one-compartment disposition model with two clearance pathways, non-renal (0.35 L/h) and renal (0.43 L/h) described cycloserine pharmacokinetics well. Non-renal clearance and volume were allometrically scaled using fat-free mass. Smoking increased non-renal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1000 mg for patients weighing ≤ 45 kg and \\textgreater 45 kg, respectively), the probability of maintaining plasma cycloserine above the MIC (T \\textgreaterMIC ) for more than 30% of the dosing interval (which is associated with a 1.0 log 10 CFU/mL kill in vitro ) exceeds, 90% at MIC values ≤ 16 mg/L, but the proportion of patients achieving 100% T \\textgreaterMIC (which is associated with prevention of resistance) is more than 90% only with MICs ≤ 8 mg/L. Based on a target derived in vitro , the WHO recommended doses of terizidone are effective for cycloserine MICs ≤ 8 mg/L and higher doses are required to prevent the development of resistance.","author":[{"propositions":[],"lastnames":["Chirehwa"],"firstnames":["Maxwell"],"suffixes":[]},{"propositions":[],"lastnames":["Court"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["De Kock"],"firstnames":["Mariana"],"suffixes":[]},{"propositions":[],"lastnames":["Wiesner"],"firstnames":["Lubbe"],"suffixes":[]},{"propositions":["de"],"lastnames":["Vries"],"firstnames":["Nihal"],"suffixes":[]},{"propositions":[],"lastnames":["Harding"],"firstnames":["Joseph"],"suffixes":[]},{"propositions":[],"lastnames":["Gumbo"],"firstnames":["Tawanda"],"suffixes":[]},{"propositions":[],"lastnames":["Maartens"],"firstnames":["Gary"],"suffixes":[]},{"propositions":[],"lastnames":["Warren"],"firstnames":["Rob"],"suffixes":[]},{"propositions":[],"lastnames":["Denti"],"firstnames":["Paolo"],"suffixes":[]},{"propositions":[],"lastnames":["McIlleron"],"firstnames":["Helen"],"suffixes":[]}],"doi":"10.1128/aac.01381-20","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chirehwa et al. - 2020 - Population pharmacokinetics of cycloserine, and pharmacokineticpharmacodynamic target attainment, in MDR-tuberc.pdf:pdf","issn":"0066-4804","journal":"Antimicrobial Agents and Chemotherapy","keywords":"original","mendeley-tags":"original","month":"aug","number":"11","pages":"e01381–20","pmid":"32816738","publisher":"American Society for Microbiology","title":"Population pharmacokinetics of cycloserine, and pharmacokinetic/pharmacodynamic target attainment, in MDR-tuberculosis patients dosed with terizidone","url":"https://aac.asm.org/content/early/2020/08/11/AAC.01381-20 https://aac.asm.org/content/early/2020/08/11/AAC.01381-20.abstract","volume":"64","year":"2020","bibtex":"@article{Chirehwa2020,\r\nabstract = {Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis. 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Simulations showed that with daily doses of terizidone (750 mg and 1000 mg for patients weighing ≤ 45 kg and {\\textgreater} 45 kg, respectively), the probability of maintaining plasma cycloserine above the MIC (T {\\textgreater}MIC ) for more than 30{\\%} of the dosing interval (which is associated with a 1.0 log 10 CFU/mL kill in vitro ) exceeds, 90{\\%} at MIC values ≤ 16 mg/L, but the proportion of patients achieving 100{\\%} T {\\textgreater}MIC (which is associated with prevention of resistance) is more than 90{\\%} only with MICs ≤ 8 mg/L. 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