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Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis

Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the do...

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Autores principales: Alghamdi, Wael A., Alsultan, Abdullah, Al-Shaer, Mohammad H., An, Guohua, Ahmed, Shahriar, Alkabab, Yosra, Banu, Sayera, Barbakadze, Ketevan, Houpt, Eric, Kipiani, Maia, Mikiashvili, Lali, Schmidt, Stephan, Heysell, Scott K., Kempker, Russell R., Cegielski, J. Peter, Peloquin, Charles A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496076/
https://www.ncbi.nlm.nih.gov/pubmed/30858211
http://dx.doi.org/10.1128/AAC.00055-19
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author Alghamdi, Wael A.
Alsultan, Abdullah
Al-Shaer, Mohammad H.
An, Guohua
Ahmed, Shahriar
Alkabab, Yosra
Banu, Sayera
Barbakadze, Ketevan
Houpt, Eric
Kipiani, Maia
Mikiashvili, Lali
Schmidt, Stephan
Heysell, Scott K.
Kempker, Russell R.
Cegielski, J. Peter
Peloquin, Charles A.
author_facet Alghamdi, Wael A.
Alsultan, Abdullah
Al-Shaer, Mohammad H.
An, Guohua
Ahmed, Shahriar
Alkabab, Yosra
Banu, Sayera
Barbakadze, Ketevan
Houpt, Eric
Kipiani, Maia
Mikiashvili, Lali
Schmidt, Stephan
Heysell, Scott K.
Kempker, Russell R.
Cegielski, J. Peter
Peloquin, Charles A.
author_sort Alghamdi, Wael A.
collection PubMed
description Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the dosing of cycloserine. TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC of ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA. Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA were achieved as the total daily dose was increased. The highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/liter. For MICs of >16 mg/liter, doses of at least 500 mg three times daily or 750 mg twice daily were needed. In conclusion, the current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs of >16mg/liter. Further studies are needed regarding the efficacy and tolerability of daily doses of >1,000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimizing exposure, which can potentially reduce adverse drug effects.
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spelling pubmed-64960762019-10-25 Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis Alghamdi, Wael A. Alsultan, Abdullah Al-Shaer, Mohammad H. An, Guohua Ahmed, Shahriar Alkabab, Yosra Banu, Sayera Barbakadze, Ketevan Houpt, Eric Kipiani, Maia Mikiashvili, Lali Schmidt, Stephan Heysell, Scott K. Kempker, Russell R. Cegielski, J. Peter Peloquin, Charles A. Antimicrob Agents Chemother Clinical Therapeutics Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the dosing of cycloserine. TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC of ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA. Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA were achieved as the total daily dose was increased. The highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/liter. For MICs of >16 mg/liter, doses of at least 500 mg three times daily or 750 mg twice daily were needed. In conclusion, the current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs of >16mg/liter. Further studies are needed regarding the efficacy and tolerability of daily doses of >1,000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimizing exposure, which can potentially reduce adverse drug effects. American Society for Microbiology 2019-04-25 /pmc/articles/PMC6496076/ /pubmed/30858211 http://dx.doi.org/10.1128/AAC.00055-19 Text en Copyright © 2019 Alghamdi et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Clinical Therapeutics
Alghamdi, Wael A.
Alsultan, Abdullah
Al-Shaer, Mohammad H.
An, Guohua
Ahmed, Shahriar
Alkabab, Yosra
Banu, Sayera
Barbakadze, Ketevan
Houpt, Eric
Kipiani, Maia
Mikiashvili, Lali
Schmidt, Stephan
Heysell, Scott K.
Kempker, Russell R.
Cegielski, J. Peter
Peloquin, Charles A.
Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title_full Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title_fullStr Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title_full_unstemmed Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title_short Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
title_sort cycloserine population pharmacokinetics and pharmacodynamics in patients with tuberculosis
topic Clinical Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496076/
https://www.ncbi.nlm.nih.gov/pubmed/30858211
http://dx.doi.org/10.1128/AAC.00055-19
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