Population Pharmacokinetics and Dose Evaluation of Cycloserine among Patients with Multidrug-Resistant Tuberculosis under Standardized Treatment Regimens

Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment....

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Published in:Antimicrobial agents and chemotherapy Vol. 67; no. 5; p. e0170022
Main Authors: Zhu, Yue, Zhu, Limei, Davies Forsman, Lina, Paues, Jakob, Werngren, Jim, Niward, Katarina, Schön, Thomas, Bruchfeld, Judith, Xiong, Haiyan, Alffenaar, Jan-Willem, Hu, Yi
Format: Journal Article
Language:English
Published: United States 17.05.2023
Subjects:
Antitubercular Agents - pharmacokinetics
Cycloserine - pharmacokinetics
Cycloserine - therapeutic use
Humans
Microbial Sensitivity Tests
Prospective Studies
Tuberculosis, Multidrug-Resistant - drug therapy
dosing evaluation
multidrug-resistant tuberculosis
cycloserine
drug concentration thresholds
minimum inhibitory concentration
population pharmacokinetics
ISSN:1098-6596, 1098-6596
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Summary:Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T ) of 30% and a ratio of area under drug concentration-time curve (AUC ) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and ≥45 kg), the probability of target attainment exceeded 90% at MIC ≤16 mg/L in MGIT for both T of 30% and AUC /MIC of 36. New clinically relevant PK/PD thresholds for cycloserine were identified in patients with standardized MDR-TB treatment. WHO-recommended doses were considered adequate for the MGIT MIC distribution in our cohort of Chinese patients with MDR-TB.
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ISSN:1098-6596
1098-6596
DOI:10.1128/aac.01700-22