Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772.

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

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.

Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.

The identification of sensitive, specific, and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time to positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis, measures longitudinal bacterial growth in mycobacterial growth indicator tube broth culture and may be predictive of standard time to stable culture conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Studies 29 and 29X), 662 participants had sputum collected over 6 months where TTP, TSCC, and time to culture conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacillus smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2b study designs. The TTP model built depicts a novel phase 2b surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT00694629 and NCT01043575.).

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

INTRODUCTION: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349. MATERIAL AND METHODS: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach. RESULTS: An Interrupted Time-Series (ITS) analysis showed a 15.4% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process. DISCUSSION: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.