Dataset Information

Bedaquiline for multidrug-resistant TB in paediatric patients.

ABSTRACT: BACKGROUND: TMC207-C211 (NCT02354014) is a Phase 2, open-label, multicentre, single-arm study to evaluate pharmacokinetics, safety/tolerability, antimycobacterial activity and dose selection of bedaquiline (BDQ) in children (birth to <18 years) with multidrug-resistant-TB (MDR-TB).METHODS: Patients received 24 weeks' BDQ with an anti-MDR-TB background regimen (BR), followed by 96 weeks of safety follow-up. Results of the primary analysis are presented based on data up to 24 weeks for Cohort 1 (≥12-<18 years; approved adult tablet at the adult dosage) and Cohort 2 (≥5-<12 years; age-appropriate 20 mg tablet at half the adult dosage).RESULTS: Both cohorts had 15 patients, of whom respectively 53% and 40% of Cohort 1 and Cohort 2 children had confirmed/probable pulmonary MDR-TB. Most patients completed 24 weeks´ BDQ/BR treatment (Cohort 1: 93%; Cohort 2: 67%). Geometric mean BDQ area under the curve _168h values of 119,000 ng.h/mL (Cohort 1) and 118,000 ng.h/mL (Cohort 2) at Week 12 were within 60-140% (86,200-201,000 ng.h/mL) of adult target values. Few adverse event (AE) related discontinuations or serious AEs, and no QTcF >460 ms during BDQ/BR treatment or deaths occurred. Of MGIT-evaluable patients, 6/8 (75%) Cohort 1 and 3/3 (100%) Cohort 2 culture converted.CONCLUSION: In children and adolescents aged ≥5-<18 years with MDR-TB, including pre-extensively drug-resistant-TB (pre-XDR-TB) or XDR-TB, 24 weeks of BDQ provided a comparable pharmacokinetic and safety profile to adults.

SUBMITTER: Moodliar R

PROVIDER: S-EPMC8412106 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Bedaquiline for multidrug-resistant TB in paediatric patients.

Moodliar R R Aksenova V V Frias M V G MVG van de Logt J J Rossenu S S Birmingham E E Zhuo S S Mao G G Lounis N N Kambili C C Bakare N N

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 20210901 9

<b>BACKGROUND:</b> TMC207-C211 (NCT02354014) is a Phase 2, open-label, multicentre, single-arm study to evaluate pharmacokinetics, safety/tolerability, antimycobacterial activity and dose selection of bedaquiline (BDQ) in children (birth to <18 years) with multidrug-resistant-TB (MDR-TB).<b>METHODS:</b> Patients received 24 weeks' BDQ with an anti-MDR-TB background regimen (BR), followed by 96 weeks of safety follow-up. Results of the primary analysis are presented based on data up to 24 weeks f ...[more]

PMID: 34802493

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Project description:Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and the development of other new drugs that are in the pipeline.

Project description:Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008-0.25 mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125 mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

Project description:Bedaquiline (BDQ), an innovative anti-tuberculous (TB) agent, has attracted attention for its potential effectiveness against drug-resistant TB. This study investigated the impact of BDQ-containing regimens on treatment success rates among multi-drug resistant tuberculosis (MDR-TB) patients in Egypt. We conducted a prospective cohort study that included all adult non-pregnant patients treated in MDR-TB centers in Egypt from April 1, 2020, to June 30, 2021, with follow-up extended until December 31, 2022. The study compared patients prescribed BDQ according to national protocols with those receiving conventional treatments for MDR-TB. Treatment success rates, mortality rates, and adverse events were analyzed using descriptive statistics, chi-square tests, logistic regression, and Kaplan-Meier survival curves. Adjustment for potential confounders was conducted using propensity score matching and Cox-hazard regressions. A total of 84 patients were included in this study. The median age of the study participants was 39 years; 22.6% were women, 57.1% were unemployed or housewives, and 1.2% had human immunodeficiency virus (HIV). Regarding the treatment regimen, 67.8% were exposed to BDQ-based treatment. Among the 55 patients (65.5%) with treatment success, a significantly higher success rate was observed in the BDQ group (73.7%) compared to the conventional group (48.1%), P = 0.042. Additionally, the incidence of skin discoloration was significantly higher in the BDQ group compared to the conventional group (38.6% versus 0.0%, P < 0.001). Despite the lower mortality incidence in the BDQ-group (14.0% versus 22.2% in the conventional group), the Kaplan-Meier survival analysis revealed no excess mortality associated with the BDQ-group, with a hazard ratio (HR) of 0.62 (95% CI 0.21-1.78, P = 0.372). Propensity score matching, while considering factors such as lesion site, diabetes mellitus, hepatitis C virus, and smoking, revealed a significant increase in the success rate associated with BDQ inclusion, with an HR of 6.79 (95% CI 1.8-25.8). In conclusion, BDQ is an effective and tolerable medication for treating MDR-TB, associated with lower mortality rates compared to conventional treatment.

Project description:BackgroundWorld Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).MethodsAEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.ResultsBy December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.ConclusionsBedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Project description:Background: The ever-growing emergence of antibiotic resistance associated with tuberculosis (TB) has become a global challenge. In 2012, the USFDA gave expedited approval to bedaquiline (BDQ) as a new treatment for drug-resistant TB in adults when no other viable options are available. BDQ is a diarylquinoline derivative and exhibits targeted action on mycobacterium tuberculosis, but due to poor solubility, the desired therapeutic action is not achieved. Objective: To develop a QbD-based self-nanoemulsifying drug delivery system of bedaquiline using various oils, surfactants, and co-surfactants. Methods: The quality target product profile (QTPP) and critical quality attributes (CQAs) were identified with a patient-centric approach, which facilitated the selection of critical material attributes (CMAs) during pre-formulation studies and initial risk assessment. Caprylic acid as a lipid, propylene glycol as a surfactant, and Transcutol-P as a co-surfactant were selected as CMAs for the formulation of bedaquiline fumarate SNEDDS. Pseudo-ternary phase diagrams were constructed to determine the optimal ratio of oil and Smix. To optimize the formulation, a Box-Benkhen design (BBD) was used. The optimized formulation (BDQ-F-SNEDSS) was further evaluated for parameters such as droplet size, polydispersity index (PDI), percentage transmittance, dilution studies, stability studies, and cell toxicity through the A549 cell. Results: Optimized BDQ-F-SNEDDS showed well-formed droplets of 98.88 ± 2.1 nm with a zeta potential of 21.16 mV. In vitro studies showed enhanced drug release with a high degree of stability at 25 ± 2 °C, 60 ± 5% and 40 ± 2 °C, 75 ± 5%. Furthermore, BDQ-F-SNEDDS showed promising cell viability in A549 cells, indicating BDQ-F-SNEDDS as a safer formulation for oral delivery. Conclusion: Finally, it was concluded that the utilization of a QbD approach in the development of BDQ-F-loaded SNEDDS offers a promising strategy to improve the biopharmaceutical properties of the drug, resulting in potential cost and time savings.

Dataset Information

Bedaquiline for multidrug-resistant TB in paediatric patients.

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Bedaquiline for multidrug-resistant TB in paediatric patients.

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