| 1. |
- Susanto, Budi Octasari, et al.
(författare)
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Rifampicin can be given as flat-dosing instead of weight-band dosing
- 2020
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 71:12, s. 3055-3060
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination (FDC) tablets according to their weight-band. However, some analysis have shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.METHODS: Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median AUC0-24h after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.RESULTS: The difference of median AUC0-24h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.CONCLUSIONS: Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.
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| 2. |
- Svensson, Elin M., 1985-, et al.
(författare)
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Model-based meta-analysis of rifampicin exposure and mortality in Indonesian tuberculous meningitis trials
- 2020
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 71:8, s. 1817-1823
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIntensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.MethodsAn individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750–1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.ResultsPharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%–6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3–2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival.ConclusionsHigher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.
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