Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

BACKGROUND: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. METHODS: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events. RESULTS: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34). CONCLUSIONS: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC

The potential for treatment shortening with higher rifampicin doses : relating drug exposure to treatment response in patients with pulmonary tuberculosis

This work was supported by the European and Developing Countries Clinical Trials partnership (grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013) and the German Ministry for Education and Research (grant 01KA0901). The original study conducted within the PanACEA consortium.Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results: Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions: Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.Publisher PDFPeer reviewe

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in &gt;50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019

Intensified antibiotic treatment of tuberculosis meningitis.

INTRODUCTION: Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 50% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcomes. AREAS COVERED: In this review, we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance, and children; and optimal research strategies. EXPERT COMMENTARY: There is good evidence from preclinical, clinical, and modeling studies to support the use of high-dose rifampicin in TBM, likely to be at least 30 mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate the use of molecular pharmacological approaches, physiologically based pharmacokinetic modeling and pharmacokinetic-pharmacodynamic studies to define optimal regimens to be tested in clinical trials. Exciting data from recent studies hold promise for improved regimens and better clinical outcomes in future

Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin

Background Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy. Methods Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10–50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. Results The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily. Conclusions Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy