Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis

Abulfathi, Ahmed A.; Decloedt, Eric H.; Svensson, Elin M; Diacon, Andreas H.; Donald, Peter R.; Reuter, Helmuth

doi:10.1007/s40262-019-00764-2

Cited by 57 publications

(51 citation statements)

References 139 publications

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“…Age, body weight, and CLCR are covariates previously shown to impact meropenem disposition, whereas, rifampicin is a potent inducer of drug metabolizing enzymes and transporters ( Du et al, 2006 ; Li et al, 2006 ; Svensson et al, 2017 ; Abulfathi et al, 2019 ; Ehmann et al, 2019 ; Rapp et al, 2020 ). For this reason, these covariates were tested first, and those found to impact meropenem disposition were included in the model as a base for further covariate exploration using stepwise covariate model (SCM) building.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, the combination of meropenem with rifampicin shows synergistic activity against not only rifampicin-sensitive Mycobacterium tuberculosis , but also against rifampicin-resistant strains in vitro ( Kaushik et al, 2015 ). Considering the important role of rifampicin in shortening treatment duration of drug-sensitive pulmonary tuberculosis to 9 months and then to 6 months when combined with pyrazinamide ( Controlled clinical trial, 1974 ; Abulfathi et al, 2019 ), any strategy that increases or even restores rifampicin susceptibility could improve treatment options in patients with drug-resistant tuberculosis .…”

Section: Introductionmentioning

confidence: 99%

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The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

et al. 2021

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

et al. 2021

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“…Two other ongoing trials attempt to shorten treatment by increasing the dose of the rifamycin, rifampin, or rifapentine. There is substantial evidence to support that rifampin dosed at the recommended 10 mg/kg is well below its therapeutic threshold and that much higher doses, even ≥35 mg/kg, may be safe and effective 1213. These studies suggest that high dose rifampin may shorten treatment based on faster rates of sputum culture conversion achieved 141516…”

Section: Active Tb Treatmentmentioning

confidence: 99%

Current and future treatments for tuberculosis

Lee

Xie

Barry

et al. 2020

BMJ

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Guidelines on the treatment of tuberculosis (TB) have essentially remained the same for the past 35 years, but are now starting to change. Ongoing clinical trials will hopefully transform the landscape for treatment of drug sensitive TB, drug resistant TB, and latent TB infection. Multiple trials are evaluating novel agents, repurposed agents, adjunctive host directed therapies, and novel treatment strategies that will increase the probability of success of future clinical trials. Guidelines for HIV-TB co-infection treatment continue to be updated and drug resistance testing has been revolutionized in recent years with the shift from phenotypic to genotypic testing and the concomitant increased speed of results. These coming changes are long overdue and are sorely needed to address the vast disparities in global TB incidence rates. TB is currently the leading cause of death globally from a single infectious agent, but the work of many researchers and the contributions of many patients in clinical trials will reduce the substantial global morbidity and mortality of the disease.

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“…Based on this exposure-response relationship, an AUC 0-24 -based target is suggested as a priority for future optimization. 17 In this context, we aimed to evaluate the current rifampicin dosing regimens for adult patients with OAI these patients, using a rifampicin population PK model and Monte Carlo simulations.…”

Section: Introductionmentioning

confidence: 99%

“…The AUC/MIC values associated with 1‐log kill for the S. aureus ATCC 25923 strain in mice was 952. Based on this exposure–response relationship, an AUC 0–24 ‐based target is suggested as a priority for future optimization 17 …”

Section: Introductionmentioning

confidence: 99%

Evaluation of current dosing guidance for oral rifampicin treatment in adult patients with osteoarticular infections

Marsot

Ménard

Dupouey

et al. 2020

Brit J Clinical Pharma

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We aimed to evaluate the actual rifampicin dosing regimens using a population pharmacokinetic model of rifampicin in patients with osteoarticular infections. A Monte Carlo simulation study was performed to simulate steady-state plasma concentrations for 1000 randomly sampled subjects using a total daily dose between 600 and 1200 mg (600 and 900 mg once daily, 450 and 600 mg twice daily, or 300 mg 3 times daily). When rifampicin was administered with fusidic acid, the pharmacokinetic/pharmacodynamic (PK/PD) target (area under the curve/minimum inhibitory concentration ≥952) was achieved with all tested dosing regimen, except 600 mg once daily for Staphylococcus epidermidis infections. Without coadministration of fusidic acid, none of tested dosing regimens achieved this PK/PD target. Most recommended drug-dosing regimens allow attaining the fixed area under the curve/minimum inhibitory concentration target for Staphylococcus aureus and coagulase-negative staphylococcal osteoarticular infections. In future studies, PK/PD target for osteoarticular infections in human should also be confirmed.

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Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis

Cited by 57 publications

References 139 publications

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

Current and future treatments for tuberculosis

Evaluation of current dosing guidance for oral rifampicin treatment in adult patients with osteoarticular infections

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