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The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis.

ABSTRACT: 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.

SUBMITTER: Svensson EM

PROVIDER: S-EPMC6005123 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis.

Svensson Elin M EM Svensson Robin J RJ Te Brake Lindsey H M LHM Boeree Martin J MJ Heinrich Norbert N Konsten Sarah S Churchyard Gavin G Dawson Rodney R Diacon Andreas H AH Kibiki Gibson S GS Minja Lilian T LT Ntingiya Nyanda E NE Sanne Ian I Gillespie Stephen H SH Hoelscher Michael M Phillips Patrick P J PPJ Simonsson Ulrika S H USH Aarnoutse Rob R

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20180601 1

<h4>Background</h4>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.<h4>Methods</h4>D ...[more]

PMID: 29917079

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Project description:BackgroundThe standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted.MethodsThis study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited.DiscussionThis study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB.Trial registrationClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

Project description:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

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The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis.

Publications

The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis.

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