Pharmacokinetic-pharmacodynamic modeling of tuberculosis time to positivity and colony-forming unit to assess the response to dose-ranging linezolid.
Antimicrob Agents Chemother
; 68(8): e0019024, 2024 Aug 07.
Article
em En
| MEDLINE
| ID: mdl-39016594
ABSTRACT
According to the World Health Organization, the number of tuberculosis (TB) infections and the drug-resistant burden worldwide increased by 4.5% and 3.0%, respectively, between 2020 and 2021. Disease severity and complexity drive the interest for undertaking new clinical trials to provide efficient treatment to limit spread and drug resistance. TB Alliance conducted a phase 2 study in 106 patients to guide linezolid (LZD) dose selection using early bactericidal activity over 14 days of treatment. LZD is highly efficient for drug-resistant TB treatment, but treatment monitoring is required since serious adverse events can occur. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to analyze the dose-response relationship between linezolid exposure and efficacy biomarkers. Using time to positivity (TTP) and colony-forming unit (CFU) count data, we developed a PKPD model in six dosing regimens, differing on LZD dosing intensity. A one-compartment model with five transit absorption compartments and non-linear auto-inhibition elimination described best LZD pharmacokinetic characteristics. TTP and CFU logarithmic scaled [log(CFU)] showed a bactericidal activity of LZD against Mycobacterium tuberculosis. TTP was defined by a model with two significant covariates the presence of uni- and bilateral cavities decreased baseline TTP value by 24%, and an increase on every 500 mg/L/h of cumulative area under the curve increased the rate at which TTP and CFU change from baseline by 20% and 11%, respectively. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT02279875.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linezolida
/
Mycobacterium tuberculosis
/
Antituberculosos
Limite:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article