Population Pharmacokinetics and Dose Evaluation of Cycloserine among Patients with Multidrug-Resistant Tuberculosis under Standardized Treatment RegimensShow others and affiliations
2023 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 67, no 5Article in journal (Refereed) Published
Abstract [en]
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. 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->MIC) of 30% and a ratio of area under drug concentration-time curve (AUC(0-24h)) 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->MIC of 30% and AUC(0-24h)/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.
Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY , 2023. Vol. 67, no 5
Keywords [en]
cycloserine; multidrug-resistant tuberculosis; minimum inhibitory concentration; population pharmacokinetics; drug concentration thresholds; dosing evaluation
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-194457DOI: 10.1128/aac.01700-22ISI: 000975278200001PubMedID: 37097151OAI: oai:DiVA.org:liu-194457DiVA, id: diva2:1764732
Note
Funding Agencies|National Natural Science Foundation of China [81874273]; Swedish Research Council; Swedish Heart and Lung Foundation; County of Stockholm; Research Council of south-eastern Sweden
2023-06-092023-06-092024-02-09