The population pharmacokinetics of meropenem in adult patients with rifampicin-sensitive pulmonary tuberculosis

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dc.contributor.authorAbulfathi, Ahmed A.en_ZA
dc.contributor.authorDe Jager, Veroniqueen_Za
dc.contributor.authorVan Brakel, Elanaen_ZA
dc.contributor.authorReuter, Helmuthen_ZA
dc.contributor.authorGupte, Nikhilen_ZA
dc.contributor.authorVanker, Naadiraen_ZA
dc.contributor.authorBarnes, Grace L.en_ZA
dc.contributor.authorNuermberger, Ericen_ZA
dc.contributor.authorDorman, Susan E.en_ZA
dc.contributor.authorDiacon, Andreas H.en_ZA
dc.contributor.authorDooley, Kelly E.en_ZA
dc.contributor.authorSvensson, Elin M.en_ZA
dc.date.accessioned2023-04-26T06:58:52Zen_ZA
dc.date.available2023-04-26T06:58:52Zen_ZA
dc.date.issued2021-06en_ZA
dc.descriptionCITATION: Abulfathi AA, de Jager V, van Brakel E, Reuter H, Gupte N, Vanker N, Barnes GL, Nuermberger E, Dorman SE, Diacon AH, Dooley KE and Svensson EM (2021) The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis. Front. Pharmacol. 12:637618. doi.10.3389/fphar.2021.637618en_ZA
dc.descriptionThe original publication is available at: frontiersin.orgen_ZA
dc.description.abstractBackground: 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.en_ZA
dc.description.versionPublisher’s versionen_ZA
dc.format.extent8 pagesen_ZA
dc.identifier.citationAbulfathi AA, de Jager V, van Brakel E, Reuter H, Gupte N, Vanker N, Barnes GL, Nuermberger E, Dorman SE, Diacon AH, Dooley KE and Svensson EM (2021) The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis. Front. Pharmacol. 12:637618. doi.10.3389/fphar.2021.637618en_ZA
dc.identifier.issn1663-9812 (online)en_ZA
dc.identifier.otherdoi.10.3389/fphar.2021.637618en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126833en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherFrontiers Media S.A.en_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectAntitubercular agentsen_ZA
dc.subjectDrugs – Pharmacokineticsen_ZA
dc.subjectPulmonary pharmacologyen_ZA
dc.subjectMultidrug-resistant tuberculosisen_ZA
dc.subjectTuberculosis -- Alternative treatmenten_ZA
dc.titleThe population pharmacokinetics of meropenem in adult patients with rifampicin-sensitive pulmonary tuberculosisen_ZA
dc.typeArticleen_ZA
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