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Background. The BACTEC Mycobacteria Growth Indicator Tube (MGIT) machine is the standard globally for detecting viable mycobacteria in patients’ sputum. Samples are observed for no longer than 42 days, at which point the sample is declared “negative” for tuberculosis (TB). This time to detection of bacterial growth, referred to as time-to-positivity (TTP), is increasingly of interest not solely as a diagnostic tool, but as a continuous biomarker wherein change in TTP can be used for comparing the bactericidal activity of different TB treatments. However, as a continuous measure, there are oddities in the distribution of TTP values observed, particularly at higher values.

Methods. We explored whether there is evidence to suggest setting an upper limit of quantification for modeling purposes (ULOQ_M) lower than the diagnostic limit of detection (LOD) using data from several TB-PACTS randomized clinical trials and PanACEA MAMS-TB.

Results. Across all trials, less than 7.1% of weekly samples returned TTP measurements between 25 and 42 days. Further, the relative absolute prediction error (%) was highest in this range. When modeling with ULOQ_Ms of 25 and 30 days, estimator precision improved for 23 of 25 regimen-level slopes compared to models using the LOD. Discrimination between regimens based on Bayesian posteriors also improved.

Conclusions. While TTP measurements between 25 days and the diagnostic LOD may be important for diagnostic purposes, TTP values in this range may not contribute meaningfully to its use as a quantitative measure, particularly when assessing treatment response, and may lead to under-powered clinical trials.

Bedaquiline has been proposed as a second-line drug to treat pulmonary disease caused by Mycobacterium avium complex. Based on in vitro synergy and interactions, a logical regimen would combine bedaquiline and clofazimine as additions to an ethambutol-azithromycin backbone. Here, we evaluate the added benefit of bedaquiline in a regimen of azithromycin, ethambutol, and clofazimine. THP-1 cells infected with M. avium ATCC 700898 were seeded in a hollow-fiber model and exposed to a regimen of azithromycin, ethambutol, and clofazimine with or without bedaquiline for 3 weeks. Epithelial lining fluid pharmacokinetic profiles of azithromycin and ethambutol were simulated, while an average steady-state concentration was sought for clofazimine and bedaquiline. Pharmacokinetics and pharmacodynamics were monitored throughout the experiment. Both regimens led to sustained bacterial killing (both intracellular and extracellular) throughout the experiment. No difference in kill rate was observed between the two therapies. The extracellular kill rate for the 3-drug regimen was 0.65 (95% CI 0.63-0.67) and for the 4-drug regimen 0.65 (95% CI 0.64-0.67). The intracellular kill rate was 0.48 (95% CI 0.46-0.50) for the 3-drug regimen and 0.48 (95% CI 0.46-0.50) for the 4-drug regimen. Macrolide-tolerant subpopulations were observed with both treatment regimens at day 21. Bedaquiline does not add killing activity to a clofazimine-ethambutol-azithromycin regimen and did not improve suppression of the emergence of macrolide resistance, which makes its role as a second-line agent doubtful.

Background: Tachycardia associated with active tuberculosis (TB) often diminishes when patients recover from TB. Elevated heart rate (HR) may lead to suboptimal correction, complicating the assessment of QT prolongation when using standard correction factors (CFs), such as Fridericia's formula (QTcF). Olliaro has proposed a CF for QT interval correction in pretreatment TB patients. However, the QT-HR correlation changes as HR decreases during treatment, indicating the need for time-varying correction.

Methods: We developed an HR model to capture the HR normalisation during successful treatment. Subsequently, a time-varying CF was constructed using the estimated HR change rate. The performance of CFs to make corrected QT (QTc) independent from HR was evaluated by linear regression analyses of QTc versus HR within defined time bins.

Results: The final HR model included asymptotic change in HR attributed to time on treatment, circadian rhythm cycles, M2 (bedaquiline-metabolite) concentration, and patient covariates. The time-varying CF decreased from 0.4081 to 0.33, with a half-life of 7.74 weeks. The slope (QTc/HR vs. Time) derived from the time-varying correction was not significantly different from 0 (95% CI -0.003 to 0.002), and the intercept was not significantly different from 0 (95% CI -0.089 to 0.006), demonstrating successful QT correction from pretreatment to the end of treatment.

Conclusion: The time-varying CF effectively captures the dynamic QT-HR relationship during TB treatment, reducing the risk of misdiagnosing QT prolongation or unnecessary discontinuation of treatment. By addressing underestimation and overestimation issues in QT interval assessment, this method enhances drug evaluation in clinical trials and supports improved treatment decisions for TB patients. (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Aims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were per- formed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses.

Results: Thirty-six children were enrolled [median age 4.8 (range 0.4–15) years and weight 15.6 (range 6.9–42.1) kg]. A two-compartment disposition model with first- order elimination and delayed absorption was developed. The bioavailability of dis- persible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95–1.15). Simulations showed WHO- recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%–56% higher doses to reach adult reference exposures.

Conclusions: Dosing recommendations for children can be the same for the dispers- ible paediatric and standard non-dispersible adult moxifloxacin formulation. The cur- rent WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.

Introduction: BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure-response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043.

Methods: A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.

Results: In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%-65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043 + M2).

Conclusions: We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.

Objective: Mycobacterium avium complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [[2], [3]]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [4]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol and azithromycin regimen using this model.

Methods: Epithelial lining fluid pharmacokinetic (PK) profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with M. avium ATCC 700898 were exposed to these regimens for 21 d. PK profiles were determined at d 0 and d 21. The pharmacodynamic effect was measured by determining bacterial densities at d 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis.

Results: The minocycline-containing regimen exhibited a 1.5 log10 CFU/mL lower bacterial burden than the recommended regimen at d 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. PK profiles simulated in the model matched those in MAC-PD patients. 

Conclusions: Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials. (c) 2024 The Author(s).

Generally, dose recommendations for children are expressed as fixed dosing increments related to bodyweight, known as weight bands. The weight bands recommended in WHO treatment guidelines vary between diseases, leading to complexity and potential dosing errors when treating children for multiple diseases simultaneously. The introduction of a harmonised weight banding approach for orally administered drugs across disease areas could streamline dosing for young children, but implementing such an approach would require changes in current dosing recommendations. In this Health Policy, we describe the process we conducted to: identify therapeutic areas for harmonisation of weight bands; propose a harmonised weight-banding system to align with current use of weight bands in antibiotic guidance; and simulate the expected effect of dose adjustments due to weight-band harmonisation. Each step of this process, along with the effect and feasibility of weight-band harmonisation was discussed with clinical, policy, and pharmacology experts convened by WHO, representing four therapeutic areas: tuberculosis, HIV, malaria, and hepatitis C. Dosing according to harmonised weight bands across the targeted therapeutic areas was found to be feasible and should be considered for implementation by WHO disease programmes through their appropriate normative processes.

Prescribing the optimal combination of anti-tuberculosis drugs at the right dose is a fundamental step to achieve successful treatment outcomes. To aid the decision, clinicians should consider multiple factors, such as body weight, age, results of drug susceptibility testing, risk of intolerance and potential drug-drug interactions. In this viewpoint, we outline different aspects of dose selection in the treatment of tuberculosis (TB) such as traditional pharmacokinetics/pharmacodynamics, population pharmacokinetics models, the importance of real-world evidence and clinical trial design in the development of shorter treatment regimens and the new TB drug pipeline. Therapeutic drug monitoring for rifampicin, linezolid and amikacin may significantly improve their risk-benefit profile promoting their responsible administration. Precision dosing of novel, repurposed or conventional TB drugs should ensure optimal efficacy, while minimising toxicity and the development of resistance.

Predicting human lung exposure with reasonable certainty of orally inhaled drugs based on preclinical studies remains a challenge for drug development. We have developed a comprehensive physiologically based pharmacokinetic (PBPK) framework tailored for the pulmonary pharmacokinetic (PK) behavior in both humans and rats, aiming to bridge the translational gap. In this study, we present a mechanistic pulmonary PBPK model for rats that integrates the pulmonary disposition processes, including drug deposition, dissolution, mucociliary clearance, and mass transfer in lung tissues. Apparent permeabilities were translated to effective permeabilities (P_eff) with in vivo–in vitro correlation methods. Unbound tissue–plasma partition coefficients for lung (K_p,u,lung) and P_eff were estimated with plasma and lung PK profiles of salbutamol and fluticasone propionate in rats. The developed PBPK model was translated by keeping the estimated parameters and switching physiological and anatomical parameters from rats to humans. Based on PK observations in rats, the estimated typical P_eff and K_p,u,lung for salbutamol were 1.18 × 10⁻⁵ cm/s and 8.83 and for fluticasone propionate 1.26 × 10⁻⁴ cm/s and 1086, respectively. After interspecies translation, the model framework well predicted the mean epithelial lining fluid concentrations following oral inhalation of salbutamol and fluticasone propionate in human subjects, with fold-errors of lung-to-plasma ratios < 2. Thus, the proposed general pulmonary PBPK framework exhibits the potential to facilitate interspecies translation and can be used to predict safety and efficacy of lung-delivered therapeutics in human.