Rifampicin flat dosing and weight-banded dosing comparable in patients with TB
The flat-dose vs weight-banded-dose cohorts did not differ with respect to TB-related unfavorable outcomes at 9, 12, and 18 months after treatment initiation.
Rifampicin 600 mg daily as a flat dose for tuberculosis (TB) is an effective and safe alternative to weight-banded dosing of rifampicin, according to study findings published in Clinical Infectious Diseases.
Researchers compared the efficacy and safety of rifampicin flat-dosing (at 600 mg daily) vs weight-banded dosing (450 mg for patients weighing 40-54 kg and 600 mg for those weighing ≥55 kg) in patients with TB.
The analysis was based on data from S31/A5349 (ClinicalTrials.gov Identifier: NCT02410772), a phase 3 trial demonstrating the noninferiority of a 4-month regimen of rifapentine-moxifloxacin to a standard 6-month control regimen. In this trial, all participants in the control arm received 600 mg daily rifampicin as a flat dose.
For the current analysis, the researchers created a virtually constructed cohort by combining data from participants in the S31/A5349 trial (who were aged 12 years and older with drug-susceptible pulmonary TB) with data from 4 other clinical trials. The analysis included 722 participants from the S31/A5349 trial with rifampicin pharmacokinetic (PK) data available, with 2108 evaluable PK samples and 480 (23%) below limit of quantification samples.
The time to TB-related unfavorable outcomes was the primary efficacy outcome, and the primary safety outcome was any adverse event of grade 3 or greater in the on-treatment period.
Sex, race, and body weight were the most important covariates associated with variability in clearance and volume of distribution. The final model showed that the median steady state area under the concentration time curve (AUCss) of male participants was about 30% lower compared with female patients, and the median AUCss of Black or mixed-race participants was about 40% lower vs Asian participants. The median AUCss of patients weighing 40 to 54 kg, 55 to 70 kg, and more than 70 kg was 48.3, 35.2, and 33.0 mg·h/L, respectively.
The flat-dosing strategy resulted in median AUCss values of 43.1 (90% CI, 21.6-87.1), 35.8 (90% CI, 18.1-71.1), and 30.4 (90% CI, 15.2-61.4) mg h/L for the weight bands of 40 to 54, 55 to 70, and more than 70 kg, respectively. The weight-banded dosing strategy yielded median AUCss values of 32.3 (90% CI, 16.2-65.3), 35.8 (90% CI, 18.2-70.9), and 30.5 (90% CI, 15.2 -61.2) mg h/L for the 3 corresponding weight bands, respectively.
The safety analysis included 722 participants with PK data, and 680 patients from the microbiologically eligible population were in the efficacy and tolerability analyses. After dichotomization of participants with rifampicin AUCss less than the median vs those greater than the median, no evidence was observed that the 2 groups were different for stable culture conversion at 6 months (1.07; 95% CI, 0.91-1.25) after treatment initiation and TB-related unfavorable outcomes (9 months [0.40; 95% CI, 0.08-2.11], 12 months [0.44; 95% CI, 0.15-1.26], and 18 months [0.73; 95% CI, 0.29-1.82] after treatment initiation).
In multivariable analysis with adjustment for pyrazinamide AUCss, age, and body weight, a 5-mg h/L increase in rifampicin AUCss had a significant association with serum total bilirubin of at least 3 time the upper limit of normal (ULN) (adjusted odds ratio 1.36; 95% CI, 1.18-1.64).
Among several limitations, the trial did not enroll participants weighing less than 40 kg, a few patients had comorbidities such as HIV and diabetes, and minimum inhibitory concentration data were unavailable.
“Collectively, PK, safety, and efficacy data supported the flat-dosing strategy in the standard 6-month regimen for the treatment of drug-susceptible TB,” the investigators stated. “Future research should assess the optimal dosing strategy for higher-dose rifampicin regimens.”
Disclosure: Sanofi donated all the study drugs in this trial, supported shipping of study drugs to all sites, and provided funding support for pharmacokinetic testing and preparation of the final clinical study report. One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
References:
Ngo HX, Xu AY, Velásquez GE, et al. Pharmacokinetic-pharmacodynamic evidence from a phase 3 trial to support flat-dosing of rifampicin for tuberculosis. Clin Infect Dis. Published online March 11, 2024. doi:10.1093/cid/ciae119
Source: Pulmonology Advisor
