Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis - PubMed (original) (raw)

Clinical Trial

. 2024 Jun 14;78(6):1680-1689.

doi: 10.1093/cid/ciae119.

Ava Y Xu 1 2, Gustavo E Velásquez 3 4, Nan Zhang 1, Vincent K Chang 1, Ekaterina V Kurbatova 5, William C Whitworth 5, Erin Sizemore 5, Kia Bryant 5, Wendy Carr 5, Marc Weiner 6, Kelly E Dooley 7, Melissa Engle 6, Susan E Dorman 8, Payam Nahid 3, Susan Swindells 9, Richard E Chaisson 10, Pheona Nsubuga 11, Madeleine Lourens 12, Rodney Dawson 13, Radojka M Savic 1 3

Affiliations

Clinical Trial

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis

Huy X Ngo et al. Clin Infect Dis. 2024.

Abstract

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

Methods: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression.

Results: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events.

Conclusions: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.

Keywords: flat-dosing; population pharmacokinetics; rifampicin; tuberculosis; weight-banded dosing.

© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.

Figure 1.

Observed rifampicin concentration over time after dose. In the top panel, the population's median plasma concentration trajectory is shown as a solid line, with LLOQ at 0.1 mg/L (dashed line). In the bottom panel, the median percentage of samples BLQ are shown as a solid line. The following bins were used to calculate the median values: 0.5 to 3, 3–8, and 8–20 hours. Abbreviations: BLQ, below the limit of quantification; LLOQ, lower limit of quantification.

Figure 2.

Figure 2.

Visual predictive check of the final population PK model in the analysis cohort (A), validation cohort (B), and full cohort (C). In the top panels, model predictions (gray-shaded area [median] and blue-shaded area [95th percentile]) are shown overlaid with observations (solid black line [median] and dashed black line [95th percentile]) with LLOQ at 0.1 mg/L. Dots represent individual observed rifampicin concentrations. In the bottom panels, model-predicted median percentages of samples BLQ (blue shaded area) are shown overlaid with observations (black solid line). The following bins were used to calculate the summary statistics: 0.5–3, 3–8, and 8–20 hours. The observed fifth-percentile data were removed due to high percentages of BLQ at 0.5 and 15.5 hours after dose. Abbreviations: BLQ, below the limit of quantification; LLOQ, lower limit of quantification; PK, pharmacokinetics.

Figure 3.

Figure 3.

Model-derived rifampicin exposure stratified by significant covariates (body weight, sex, and race). Dots and bars represent stratified medians and ranges (5th to 95th percentiles) for each subpopulation. The size of dots shown corresponds to the number of participants. The dashed horizontal line corresponds to median exposure of entire population or fold change of 1 (41.8 mg·h/L). Abbreviation: AUCss, area under the plasma concentration-time curve at steady state.

Figure 4.

Figure 4.

Comparable exposure from 600 mg rifampicin given as flat-dosing and weight-banded dosing. A total of 500 simulations were performed using a virtual population of persons with TB (N = 5687) consisting of demographic factors from 4 trials: S31/A5349 (NCT02410772), OFLOTUB (NCT00216385), REMoxTB (NCT00864383), and RIFAQUIN (ISRCTN44153044). In the standard 6-month control regimen, the flat-dosing strategy means administering rifampicin at 600 mg daily, while weight-banded dosing strategy means administering rifampicin daily based on weight bands (450 mg for patients weighing 40–50 kg and 600 mg for those weighing ≥55 kg). Abbreviations: AUCss area under the plasma concentration-time curve at steady state; TB, tuberculosis.

Figure 5.

Figure 5.

Cumulative event curves for (A) time to stable culture conversion at 6 months and (B) time to TB-related unfavorable outcomes at 12 months stratified by median exposure of rifampicin. Hazard ratios and P values were adjusted for HIV status, Xpert MTB/RIF cycle threshold, extent of disease on chest radiograph, and site (African vs non-African site). Abbreviations: AUCss, area under the plasma concentration-time curve at steady state; HIV, human immunodeficiency virus; HR, hazard ratio; TB, tuberculosis.

Figure 6.

Figure 6.

Odds of safety outcomes by rifampicin exposure. Odds ratios were calculated per 5-mg·h/L increase in rifampicin AUCss after adjustment for pyrazinamide AUCss, age, and body weight. The safety outcome is highlighted in orange if it was found to be statistically significant with a P value <.05. Safety and tolerability outcomes were defined as those occurring during treatment and up to 14 days after discontinuation of study drug. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUCss, area under the plasma concentration-time curve at steady state; CI, confidence interval; n/N, number of participants reported for each safety outcome over of the total number of participants analyzed; ULN, upper limit of normal.

References

    1. Iacobino A, Piccaro G, Giannoni F, Mustazzolu A, Fattorini L. Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli. Int J Mycobacteriol 2017; 6:213–21. -PubMed
    1. Van Ingen J, Aarnoutse RE, Donald PR, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis 2011; 52:e194–199. -PubMed
    1. World Health Organization . Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, Switzerland: World Health Organization, 2020. -PubMed
    1. World Health Organization . WHO consolidated guidelines on tuberculosis. Module 4: treatment drug-susceptible tuberculosis treatment. Geneva, Switzerland: World Health Organization, 2022. -PubMed
    1. Susanto BO, Svensson RJ, Svensson EM, Aarnoutse R, Boeree MJ, Simonsson USH. Rifampicin can be given as flat-dosing instead of weight-band dosing. Clin Infect Dis 2020; 71:3055–60. -PMC -PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources