Abstract
Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
Highlights
The epidemic rise in multi-drug resistant (MDR) and extensively drug resistant tuberculosis (XDR-TB) threatens the progress made in reducing morbidity, mortality, and efforts in tuberculosis eradication (WHO Guideline, 2019)
Whereas 34 plasma samples were below the quantification limit (BQL), three samples were excluded with the motivation that the concentrations were at least 10-fold higher than expected, and their conditional weighted residuals (CWRES) ≥4
We describe for the first time, the population pharmacokinetics of meropenem in patients with tuberculosis
Summary
The epidemic rise in multi-drug resistant (MDR) and extensively drug resistant tuberculosis (XDR-TB) threatens the progress made in reducing morbidity, mortality, and efforts in tuberculosis eradication (WHO Guideline, 2019). Mycobacterium tuberculosis is historically considered resistant to β-lactam antibiotics including carbapenems because of the constitutive production of a broad-spectrum β-lactamase called BlaC (Solapure et al, 2013; van Rijn et al, 2019). The addition of a β-lactamase inhibitor such as clavulanate prevents BlaC-mediated breakdown of β-lactams (van Rijn et al, 2019). Recent evidence from in vitro and in vivo experiments shows that carbapenems including meropenem in combination with amoxicillin/clavulanate have synergistic antimycobacterial activity (Hugonnet et al, 2009; Solapure et al, 2013). The combination of meropenem with rifampicin shows synergistic activity against rifampicin-sensitive Mycobacterium tuberculosis, and against rifampicin-resistant strains in vitro (Kaushik et al, 2015). This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
