Pharmacokinetic–pharmacodynamic modeling of tuberculosis time to positivity and colony-forming unit to assess the response to dose-ranging linezolid

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