Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Brake, Lindsey H.M. te; Ruslami, Rovina; Later-Nijland, H.; Mooren, Fieke; Teulen, Marga; Apriani, Lika; Koenderink, Jan B.; Rüssel, Frans G. M.; Burger, David M.; Alisjahbana, Bachti; Wieringa, Frank T.; Crevel, Reinout van; Aarnoutse, R.E.

doi:10.1128/aac.03485-14

Cited by 22 publications

(11 citation statements)

References 40 publications

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“…These results are in agreement with data from the literature showing that individual or mean rifampin CSF concentrations Ͼ1 mg/liter are rare (15)(16)(17)(18). Due to its protein binding in plasma (19), only 15% to 20% of rifampin is available for transport to other tissues, and penetration to the brain is even more limited.…”

Section: Discussionsupporting

confidence: 91%

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

Dian

Yunivita

Ganiem

et al. 2018

Antimicrob Agents Chemother

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High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively ( = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.).

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Section: Discussionsupporting

confidence: 91%

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

Dian

Yunivita

Ganiem

et al. 2018

Antimicrob Agents Chemother

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“…The resulting IC 50 values of ∼1 μM for both OATP1B1 and Oatp1b2 were similar to those reported previously for uptake inhibition by rifampin of other substrates . As plasma C max of unbound rifampin is ∼1.3 μM (1.1 mg/L), the intrinsic likelihood of an OATP1B1‐mediated pharmacokinetic drug–drug interaction between rifampin and SG is high.…”

Section: Resultssupporting

confidence: 85%

Influence of OATP1B1 Function on the Disposition of Sorafenib‐β‐D‐Glucuronide

Bins

Doorn

Phelps

et al. 2017

Clinical Translational Sci

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The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9‐mediated formation of sorafenib‐β‐D‐glucuronide (SG). Using transporter‐deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver‐to‐blood shuttling loop via ABCC3‐mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B‐type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2‐deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug–drug interaction studies of agents that undergo extensive phase II conjugation.

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“…(16, 17 These results are in agreement with data from the literature showing that individual or mean rifampicin CSF concentrations above 1 mg/L are rare. (17–20) Due to its protein binding in plasma, (21) only 15–20% of rifampicin is available to be transported to other tissues, and penetration to the brain is even more limited.…”

Section: Discussionmentioning

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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Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Cited by 22 publications

References 40 publications

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

Influence of OATP1B1 Function on the Disposition of Sorafenib‐β‐D‐Glucuronide

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

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