Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients

Yunivita, Vycke; Dian, Sofiati; Ganiem, Ahmad Rizal; Hayati, Ela; Achmad, Tri Hanggono; Dewi, Atu Purnama; Teulen, Marga; Meijerhof-Jager, Petra; Crevel, Reinout van; Aarnoutse, Rob E.; Ruslami, Rovina

doi:10.1016/j.ijantimicag.2016.06.016

Cited by 54 publications

(48 citation statements)

References 18 publications

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“…The model developed here predicted an increase in plasma C max from 11.9 mg/L (10 mg/kg) to 20. 8 The day 9 predicted estimates for AUC and C max were also similar to the values reported by Dian and Yunvita, indicating that the rifampin dose used in our trial had the predicted increase in exposure.…”

Section: Discussionsupporting

confidence: 86%

“…4 Clinical and pharmacological studies conducted in Indonesian adults with TBM have suggested that survival increases with increased drug exposure and rifampin doses of at least 20 mg/kg, and possibly up to 35 mg/kg/day, may be required to improve outcomes. [5][6][7][8] Taken together, these studies suggest the rifampin dose used in our trial (15 mg/kg/day) may have been too low.…”

mentioning

confidence: 77%

“…Evidence has accumulated that higher rifampin exposure is associated with increased survival from TBM. [5][6][7][8] A recent study suggested that exceeding a threshold value of plasma AUC 0-6 of 70 mg·hour/L (AUC 0-24 116 mg·hour/L) and a C max of 22 mg/L in the first 3 days of rifampin administration is associated with increased survival. 7 In our trial, the thresholds were not met for C max or AUC in 99.2% (117/118) and 90.7% (107/118) of patients given 10 mg/kg rifampin.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

Ding

Thuong

Pham

et al. 2020

Clin Pharma and Therapeutics

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The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure–response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2–93.8) to 82.5 hour·mg/L (range 8.7–161.0) in plasma and from 3.5 hour·mg/L (range 1.2–9.6) to 6.0 hour·mg/L (range 0.7–15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

Ding

Thuong

Pham

et al. 2020

Clin Pharma and Therapeutics

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“…Based on a previous clinical trial, the number of participants needed per study arm to estimate the total exposure to rifampicin (AUC 0-24h ) at a dose of 20 mg/kg, using 95% confidence and a margin of error of 20%, was n=18 for days 2±1 and n=16 at day 10±1. (11) Considering dropouts, 20 patients were needed for each study arm. This number of participants was also shown to be sufficient to demonstrate a significant difference in AUC 0-24h achieved after 10, 20 and 30 mg/kg of rifampicin.…”

Section: Methodsmentioning

confidence: 99%

“…Our second open-label pharmacokinetic study was conducted; doses of 17 or 20 mg/kg of oral rifampicin resulted in average total exposures in plasma (area under the concentration versus time curves, AUC 0-24h ) that were approximately similar to the values after 13 mg/kg iv, but average peak plasma concentrations (C max ) were lower with large interindividual variabilities. (11)…”

Section: Introductionmentioning

confidence: 99%

A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

Dian

Yunivita

Ganiem

et al. 2018

Preprint

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29 30 Running title: high dose rifampicin in tuberculous meningitis 31 Word count: running title: 46 characters; abstract: 199 words; main text: 3487 words 32 2 ABSTRACT 33 34 Background 35High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-36 pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg 37 orally (as previously studied) are warranted to maximize treatment response. 38 Methods 39In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in 40 Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined 41 with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival. 42 Results 43A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in 44 plasma in the critical early days (21) of treatment (AUC 0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, 45 p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 46 3/4 adverse events. Six-month mortality was 7/20 (35%), 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg 47 groups, respectively (p=0·12). 48 Conclusions 49Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. 50Survival benefit with this dose should now be evaluated in a larger phase III clinical trial. 51 52 53 54 55 In 2016, the WHO published data on 10.4 million new tuberculosis (TB) cases and 1·3 million deaths caused by 57 this disease worldwide, making it the leading single infectious disease killer.(1) In turn, tuberculous meningitis 58 (TBM) is the most devastating form of TB. It occurs in 1-6% of patients with TB,(2, 3) leading to death or 59 neurological disability in more than 30% of affected patients.(2, 4, 5) 60 Antimicrobial treatment for TBM follows the model for pulmonary TB, with intensive and continuation phases 61 of treatment. It adheres to the same first-line TB drugs and dosing guidelines,(6) although it is known that some 62 first-line TB drugs, including rifampicin, achieve suboptimal concentrations beyond the blood-brain and blood-63 cerebrospinal fluid (CSF) barriers. Rifampicin is a crucial TB drug, evidenced by the high mortality rate in TBM 64 patients with resistance to rifampicin.(7, 8) As it takes a long time to develop new drugs to treat TB and TBM, it 65is important to make the best possible use of existing drugs. We performed a series of studies to evaluate higher 66 doses of rifampicin in Indonesian patients with TBM. 67A first open-label, randomised phase II clinical trial showed that a 33% higher dose of rifampicin administered 68 intravenously (13 mg/kg iv) for two weeks led to a three-fold higher exposure to rifampicin in plasma and CSF 69 during the first critical days of treatment, and a strong reduction in mortality at six months after the treatment 70 started (adjust...

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Investigating aqueous micellar systems enhancement tools for a sensitive spectrofluorimetric determination of anti‐TB: Rifampicin

El‐Aziz,

Samir Elama

2024

Luminescence

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Rifampicin is a frontline antibiotic in the management of tuberculosis. Since no spectrofluorimetric methods are reported for this drug, this approach was challenged to craft a sensitive, reliable, valid, fast, and green methodology. In recent years, fluorescence spectroscopy has received a lot of interest. Its benefits include ecological greenness and analytical performance. The pharmaceutical industries greatly like this approach because of its low energy and decreased solvent usage, which make it both economical and environmentally friendly. This methodology was based on utilizing the enhanced native fluorescence of the rifampicin at 341 nm after excitation at 241 nm in a beta‐cyclodextrin micellar system. Modern developments in analytical chemistry have been applied to reduce risks to the workplace and environment by using distilled water as a dilution solvent for method application and optimization. The method was found excellent green with 97 eco‐scale and 0.86 AGREE scores besides an 89.6 overall whiteness score. The range of linearity for rifampicin raw material was 0.2–1.5 μg·mL−1, and the average recoveries for raw material and spiked plasma were 100.15% and 99.64%, respectively. The suggested technique worked well for the commercial oral syrup of Rimactane® and did not conflict with any common additives.

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Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients

Cited by 54 publications

References 18 publications

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

Investigating aqueous micellar systems enhancement tools for a sensitive spectrofluorimetric determination of anti‐TB: Rifampicin

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