Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.

Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.

High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.

BACKGROUND: Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. METHODS AND FINDINGS: We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. CONCLUSIONS: Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.

Tuberculosis Molecular Bacterial Load Assay Reveals Early Delayed Bacterial Killing in Patients With Relapse.

Bacterial killing in patients with tuberculosis (TB) relapse was compared to that in patients achieving cure, measured by TB molecular bacterial load assay (TB-MBLA) or mycobacteria growth indicator tube (MGIT) time to positivity (TTP). TB-MBLA in 4 relapsed patients was significantly different compared to 132 cured patients after 2 weeks of treatment; MGIT TTP showed a significant difference from week 8.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians.

Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.

Optimising pyrazinamide for the treatment of tuberculosis.

Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg-1), pyrazinamide (range 20-30 mg·kg-1), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK-PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin area under the curve (p-value<0.01). Modelling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.

Increased bactericidal activity but dose-limiting intolerability at 50†mg·kg-1 rifampicin.

BACKGROUND: Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose escalation study in treatment-naive adult smear-positive patients with TB. METHODS: Patients received, in consecutive cohorts, 40 or 50 mg·kg-1 rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between days 8 and 14. RESULTS: In the 40 mg·kg-1 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg-1 cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration-time curve from time 0 to 12 h (AUC0-24 h) for 50 mg·kg-1 compared with 40 mg·kg-1; 571 (range 320-995) versus 387 (range 201-847) mg·L-1·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg-1 (11% (range 8-17%)) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg-1: 14-day EBA -0.427 (95% CI -0.500- -0.355) log10CFU·mL-1·day-1. CONCLUSION: Although associated with an increased bactericidal effect, the 50 mg·kg-1 dose was not well tolerated. Rifampicin at 40 mg·kg-1 was well tolerated and therefore selected for evaluation in a phase IIc treatment-shortening trial.

Early COVID-19 pandemic's toll on tuberculosis services, WHO European Region, January to June 2020.

BackgroundEssential health services, including for tuberculosis (TB), are being affected by public health and social measures (PHSM) introduced to control COVID-19. In many settings, TB resources, facilities and equipment are being redirected towards COVID-19 response.AimWe sought to assess the COVID-19 pandemic's impact on TB services in the World Health Organization (WHO) European Region.MethodsThe fifty-three European Region Member States were asked to report qualitative and quantitative data in quarter one and two (Q1 and Q2) 2020. TB notifications were triangulated with the severity score on domestic movement restrictions to assess how they may have influenced TB detection.ResultsTwenty-nine countries reported monthly TB notifications for the first half of 2019 and 2020. TB notifications decreased by 35.5% during Q2 2020 compared with Q2 2019, which is six-fold more than the average annual decrease of 5.1% documented during 2015-2019. The number of patients enrolled in rifampicin-resistant/multidrug-resistant TB treatment also decreased dramatically in Q2 2020, by 33.5%. The highest movement restriction severity score was observed between April and May 2020, which coincided with the highest observed decrease in TB notifications.ConclusionA decrease in TB detection and enrolment to treatment may cause increases in TB burden and threatens the Region's ability to reach the TB targets of the 2030 Sustainable Development Goals, still this might be mitigated with rapid restoration of TB services and the implementation of targeted interventions during periods with severe PHSM in place, such as those introduced in response to the COVID-19 pandemic.

Rifampicin Can Be Given as Flat-Dosing Instead of Weight-Band Dosing.

BACKGROUND: The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing. METHODS: Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median area under the curve (AUC0-24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing. RESULTS: The difference of median AUC0-24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing. CONCLUSIONS: Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.

Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay.

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=-0.51, 95% CI (-0.56 to -0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin-20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.

Accelerating the transition of new tuberculosis drug combinations from Phase II to Phase III trials: New technologies and innovative designs.

Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Protein binding of rifampicin is not saturated when using high-dose rifampicin.

BACKGROUND: Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. OBJECTIVES: To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. METHODS: Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0-24 to predict unbound AUC0-24 was evaluated. RESULTS: The in vitro free fraction of rifampicin remained unaltered (∼9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC0-24in vivo was 13.3% (range = 8.1%-24.9%) and 11.1% (range = 8.6%-13.6%) for the standard group and the high-dose group, respectively (P = 0.214). Prediction of unbound AUC0-24 based on total AUC0-24 resulted in a bias of -0.05% and an imprecision of 13.2%. CONCLUSIONS: Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.

Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients.

BACKGROUND: Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population. OBJECTIVES: To compare exposure to TB drugs in Tanzanian TB patients with and without DM. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs. RESULTS: A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid. CONCLUSIONS: There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations.

Background: The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin. Methods: Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates. Results: The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days. Conclusions: A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin. Clinical Trials Registration: NCT01392911.

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

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.

A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).

BACKGROUND: The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer. METHODS: We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. RESULTS: With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. CONCLUSIONS: Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.

A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis.

RATIONALE: Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity, and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment. OBJECTIVES: To evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin. METHODS: Patients with drug-susceptible tuberculosis were enrolled into a control group of eight patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20, 25, 30, and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide, and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed. MEASUREMENTS AND MAIN RESULTS: Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were five grade 3 events of which one was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively. CONCLUSIONS: Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a nonlinear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registered with www.clinicaltrials.gov (NCT 01392911).