A meta-analysis for predicting early bactericidal activity of beta-lactam antibiotics against pulmonary tuberculosis
Raman Sharma and Chao Chen
GlaxoSmithKline PLC.
Introduction: Tuberculosis is a leading cause of mortality among infections, with 6.4 million new diagnosis and 1.6 million deaths in 2021. [1] Better drugs for treating tuberculosis are clearly needed due to issues with adherence, tolerability and resistance associated with the currently recommended multi-drug treatment regimen. [2] Mixed results [3] from recent early bactericidal activity (EBA) phase 2a trials of β-lactams have highlighted a gap in efficacy prediction for emerging treatment candidates . Plasma pharmacokinetic-pharmacodynamic (PKPD) indices like fAUC/MIC, fCmax/MIC and fT>MIC are often used to predict the clinical efficacy of antibiotics. Here fAUC is the area under the free concentration-time curve, fCmax is the maximal free concentration, MIC is the minimal inhibitory concentration, and fT>MIC is the fraction of the time during a dosing interval when the free concentration exceeds the MIC. Previously for beta-lactams fT>MIC has been postulated as the most relevant PKPD index for predicting anti-tubercular activity based on carbapenems demonstrating bactericidal activity when the free-drug plasma concentration exceeds the MIC for at least 40% of the time (40% fT>MIC) in non-M. tuberculosis bacterial species.
Objectives: Using meta-analysis models to identify the best-performing PKPD index for predicting anti-TB EBA of beta-lactam agents in phase 2a EBA studies.
Methods and Measurements: The analysis included PKPD data from 111 patients over 11 treatment arms including several seven regimens of meropenem, faropenem, ertapenem and four additional β-lactam regimens that are anonymised here for confidentiality. All treatments are in combination with amoxicillin and clavulanic acid. [4-6] MIC values were either generated internally or identified from literature.[7] Plasma protein binding values were obtained internally from ultrafiltration experiments. Population pharmacokinetic modelling was conducted to derive steady-state free-concentration PKPD indices fCmax/MIC, fAUC/MIC, and fT>MIC for each arm. The correlation between 14-day EBA and each index was calculated across all treatment arms.
Results: Two compartment structural PK model were found to best fit the PK data for all β-lactams in-line with previous work. [6,8,9] The mean 14-day EBA for the 11 arms ranged from -0.12 (meropenem iv 2 g tid) to +0.03 (ertapenem im 1 g qd). The strongest and most significant EBA correlate was fAUC/MIC: r2=0.849 and p=0.00006. For fT>MIC, r2=0.567 and p=0.007. For fCmax/MIC, r2=0.493 and p=0.02.
Conclusion: We report a meta-analysis that identified fAUC/MIC as the primary PKPD predictor for early bactericidal activity of beta-lactam drug class in pulmonary tuberculosis. The model can be used to predict the EBA of other beta-lactams against TB. Importantly, the model established the expectation of the level of clinical pharmacology (i.e. fAUC/MIC) that will be required for future in-class drug candidates to achieve a target EBA. This approach can be applied to other classes of anti-infectives, for tuberculosis or for other indications.
Acknowledgements: We thank Andreas Diacon, Caryn Upton and Kelly Dooley, and their respective teams at TASK and Vanderbilt TB Center, for generating the clinical trial data from some of the studies included in the meta-analyses. We also thank Pablo Gamallo, Marisa Maria Santos Martinez-Martinez, Robert Bates and Joel Lelievre at GSK for their support of the project.
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