RESUMO
BACKGROUND: Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. OBJECTIVES: To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. METHODS: Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. RESULTS: A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. CONCLUSIONS: The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.
Assuntos
Antituberculosos , Diarilquinolinas , Tuberculose Pulmonar , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Resultado do Tratamento , Feminino , Diarilquinolinas/uso terapêutico , Masculino , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/mortalidade , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Mycobacterium tuberculosis/efeitos dos fármacos , Carga Bacteriana , Modelos Estatísticos , Idoso , RecidivaRESUMO
BACKGROUND: New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection. METHODS: Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months. RESULTS: B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens. CONCLUSIONS: BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.
Assuntos
Antituberculosos , Diarilquinolinas , Modelos Animais de Doenças , Quimioterapia Combinada , Camundongos Endogâmicos BALB C , Moxifloxacina , Mycobacterium tuberculosis , Nitroimidazóis , Oxazóis , Animais , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/farmacologia , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Camundongos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Oxazóis/farmacologia , Moxifloxacina/uso terapêutico , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacologia , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Oxazolidinonas/uso terapêutico , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacocinética , Pirazinamida/uso terapêutico , Pirazinamida/administração & dosagem , Resultado do Tratamento , IsoxazóisRESUMO
Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of â¼70 nm at a relatively high drug concentration (â¼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (â¼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.
Assuntos
Administração Intranasal , Antituberculosos , Diarilquinolinas , Lipossomos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis , Animais , Diarilquinolinas/farmacocinética , Diarilquinolinas/administração & dosagem , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Lipossomos/química , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/química , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Feminino , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Fucose/química , Tuberculose/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C3HRESUMO
Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.
Assuntos
Antituberculosos , Encéfalo , Pulmão , Mycobacterium tuberculosis , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Coelhos , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Tuberculose Meníngea/diagnóstico por imagem , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico por imagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.
Assuntos
Antituberculosos , Camundongos Endogâmicos BALB C , Pró-Fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/farmacocinética , Camundongos , Ratos , Testes de Sensibilidade Microbiana , Espectinomicina/farmacologia , Espectinomicina/síntese química , Espectinomicina/química , Fosfatos/química , Fosfatos/farmacologia , Fosfatos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Relação Estrutura-AtividadeRESUMO
Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility. Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40-50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130-300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.
Assuntos
Antituberculosos , Inaladores de Pó Seco , Leucina , Lipossomos , Tamanho da Partícula , Tuberculose Pulmonar , Administração por Inalação , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Tuberculose Pulmonar/tratamento farmacológico , Humanos , Leucina/química , Leucina/administração & dosagem , Trealose/química , Trealose/administração & dosagem , Aerossóis , Solubilidade , Excipientes/química , Pós , Liberação Controlada de Fármacos , Secagem por Atomização , Composição de Medicamentos/métodos , Química Farmacêutica/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , NitroimidazóisRESUMO
Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 µg/mL]. Chiral resolution was performed on compounds 5b and 5j; the isomers were evaluated for their activity and safety, confirming that the R-isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 µg/mL; MDR-Mtb: 0.125-0.06 µg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum. Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.
Assuntos
Antituberculosos , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Peixe-Zebra , Antituberculosos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Antituberculosos/química , Animais , Relação Estrutura-Atividade , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacocinética , Humanos , Mycobacterium marinum/efeitos dos fármacos , Estrutura MolecularRESUMO
Assuntos
Antituberculosos , Diabetes Mellitus , Tuberculose , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Diabetes Mellitus/metabolismo , Isoniazida/farmacocinética , Isoniazida/administração & dosagem , Pirazinamida/farmacocinética , Rifampina/farmacocinética , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológicoRESUMO
Tuberculosis (TB) is an infectious disease that primarily affects the lungs of humans and accounts for Mycobacterium tuberculosis (Mtb) bacteria as the etiologic agent. In this study, we introduce a computational framework designed to identify the important chemical features crucial for the effective inhibition of Mtb ß-CAs. Through applying a mechanistic model, we elucidated the essential features pivotal for robust inhibition. Using this model, we engineered molecules that exhibit potent inhibitory activity and introduce relevant novel chemistry. The designed molecules were prioritized for synthesis based on their predicted pKi values via the QSAR (Quantitative Structure-Activity Relationship) model. All the rationally designed and synthesized compounds were evaluated in vitro against different carbonic anhydrase isoforms expressed from the pathogen Mtb; moreover, the off-target and widely human-expressed CA I and II were also evaluated. Among the reported derivatives, 2, 4, and 5 demonstrated the most valuable in vitro activity, resulting in promising candidates for the treatment of TB infection. All the synthesized molecules exhibited favorable pharmacokinetic and toxicological profiles based on in silico predictions. Docking analysis confirmed that the zinc-binding groups bind effectively into the catalytic triad of the Mtb ß-Cas, supporting the in vitro outcomes with these binding interactions. Furthermore, molecules with good prediction accuracies according to previously established mechanistic and QSAR models were utilized to delve deeper into the realm of systems biology to understand their mechanism in combating tuberculotic pathogenesis. The results pointed to the key involvement of the compounds in modulating immune responses via NF-κß1, SRC kinase, and TNF-α to modulate granuloma formation and clearance via T cells. This dual action, in which the pathogen's enzyme is inhibited while modulating the human immune machinery, represents a paradigm shift toward more effective and comprehensive treatment approaches for combating tuberculosis.
Assuntos
Anidrases Carbônicas , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Humanos , Anidrases Carbônicas/metabolismo , Anidrases Carbônicas/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Relação Quantitativa Estrutura-Atividade , Simulação de Acoplamento Molecular , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Modelos BiológicosRESUMO
Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.
Assuntos
Antituberculosos , Isoniazida , Mycobacterium tuberculosis , Medicina de Precisão , Tuberculose , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Medicina de Precisão/métodos , Isoniazida/farmacocinética , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Monitoramento de Medicamentos/métodos , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Farmacogenética , Farmacorresistência Bacteriana/genéticaRESUMO
According to the World Health Organization, the number of tuberculosis (TB) infections and the drug-resistant burden worldwide increased by 4.5% and 3.0%, respectively, between 2020 and 2021. Disease severity and complexity drive the interest for undertaking new clinical trials to provide efficient treatment to limit spread and drug resistance. TB Alliance conducted a phase 2 study in 106 patients to guide linezolid (LZD) dose selection using early bactericidal activity over 14 days of treatment. LZD is highly efficient for drug-resistant TB treatment, but treatment monitoring is required since serious adverse events can occur. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to analyze the dose-response relationship between linezolid exposure and efficacy biomarkers. Using time to positivity (TTP) and colony-forming unit (CFU) count data, we developed a PKPD model in six dosing regimens, differing on LZD dosing intensity. A one-compartment model with five transit absorption compartments and non-linear auto-inhibition elimination described best LZD pharmacokinetic characteristics. TTP and CFU logarithmic scaled [log(CFU)] showed a bactericidal activity of LZD against Mycobacterium tuberculosis. TTP was defined by a model with two significant covariates: the presence of uni- and bilateral cavities decreased baseline TTP value by 24%, and an increase on every 500 mg/L/h of cumulative area under the curve increased the rate at which TTP and CFU change from baseline by 20% and 11%, respectively. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02279875.
Assuntos
Antituberculosos , Linezolida , Mycobacterium tuberculosis , Linezolida/farmacocinética , Linezolida/farmacologia , Linezolida/administração & dosagem , Humanos , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Adulto , Masculino , Feminino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Relação Dose-Resposta a Droga , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Contagem de Colônia MicrobianaRESUMO
INTRODUCTION: Isoniazid is a first-line antituberculosis agent with high variability, which would profit from individualized dosing. Concentrations of isoniazid at 2 h (C2h), as an indicator of safety and efficacy, are important for optimizing therapy. OBJECTIVE: The objective of this study was to establish machine learning (ML) models to predict the C2h, that can be used for establishing an individualized dosing regimen in clinical practice. METHODS: Published population pharmacokinetic (PopPK) models for adults were searched based on PubMed and ultimately four reliable models were selected for simulating individual C2h datasets under different conditions (demographics, genotype, ethnicity, etc.). Machine learning models were trained on simulated C2h obtained from the four PopPK models. Five different algorithms were used for ML model building to predict C2h. Real-world data were used for predictive performance evaluations. Virtual trials were used to compare ML-optimized doses with PopPK model-optimized doses. RESULTS: Categorical boosting (CatBoost) exhibited the highest prediction ability. Target C2h can be predicted using the ML model combined with the dosing regimen and three covariates (N-acetyltransferase 2 [NAT2] genotypes, weight and race [Asians and Africans]). Real-world data validation results showed that the ML model can achieve an overall prediction accuracy of 93.4%. Using the final ML model, the mean absolute prediction error value decreased by 45.7% relative to the average of PopPK models. Using the ML-optimized dosing regimen, the probability of target attainment increased by 43.7% relative to the PopPK model-optimized dosing regimens. CONCLUSION: Machine learning models were developed with great predictive performance, which can be used to determine the individualized initial dose of isoniazid in adult patients.
Assuntos
Antituberculosos , Isoniazida , Aprendizado de Máquina , Tuberculose , Humanos , Isoniazida/farmacocinética , Isoniazida/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Tuberculose/tratamento farmacológico , Modelos Biológicos , Adulto , Medicina de Precisão/métodos , Relação Dose-Resposta a Droga , Arilamina N-Acetiltransferase/genética , AlgoritmosRESUMO
Every year, the World Health Organization reports 500,000 new cases of drug-resistant tuberculosis (TB), which poses a serious global danger. The increased number of XDR-TB and MDR-TB cases reported worldwide necessitates the use of new therapeutic approaches. The main issues with the antitubercular medications now in use for the treatment of multidrug-resistant tuberculosis are their poor side effect profile, reduced efficacy, and antimicrobial resistance. One possible remedy for these problems is bedaquiline. The need for better treatment strategies is highlighted by the strong minimum inhibitory concentrations that bedaquiline (BDQ), a novel anti-TB medicine, exhibits against both drug-resistant and drug-susceptible TB. Bedaquiline may be able to help with these problems. Bedaquiline is a medication that is first in its class and has a distinct and particular mode of action. Bedaquiline is an ATP synthase inhibitor that is specifically directed against Mycobacterium tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4. Bedaquiline preclinical investigations revealed intralesional drug biodistribution. The precise intralesional and multi-compartment pharmacokinetics of bedaquiline were obtained using PET bioimaging and high-resolution autoradiography investigations. Reduced CFU counts were observed in another investigation after a 12-week course of therapy. Meta-analyses and systematic reviews of phase II trials on bedaquiline's efficacy in treating drug-resistant tuberculosis in patients reported higher rates of cure, better culture conversion, and lower death rates when taken in conjunction with a background regimen. Here is a thorough medication profile for bedaquiline to aid medical professionals in treating individuals with tuberculosis.
Assuntos
Antituberculosos , Diarilquinolinas , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacocinética , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , AnimaisRESUMO
This study aimed to assess the safety, pharmacokinetics, and food impact on sudapyridine (WX-081), a novel drug designed to inhibit mycobacterium ATP synthase, with clinical applications for drug-resistant tuberculosis (TB) treatment. The research comprised two arms: a single ascending dose (SAD) arm (30 to 600 mg, N = 52) and a multiple ascending dose (MAD) arm (200 to 400 mg, N = 30). The influence of food was evaluated using a 400 mg dose within an SAD cohort. Plasma concentrations of WX-081 and M3 (main metabolite of WX-081) were analyzed using a validated liquid-chromatography tandem mass spectrometry method. In the SAD arm, mean residence time (MRT0-t), terminal half-life, and clearance of WX-081 ranged from 18.87 to 52.8 h, 31.39 to 236.57 h, and 6.4 to 80.34 L/h, respectively. The area under the curve from time zero to the last measurable timepoint (AUC0-t) of WX-081 showed dose-proportional increases in the SAD arm. The disparity between fasted and fed states of WX-081 was significant (p < 0.05), with fed dosing resulting in a 984.07% higher AUC0-t and 961.55% higher maximum plasma concentration. In both the SAD and MAD arms, one case each exhibited a 1 degree atrioventricular block. No QTc elongation was observed, and adverse events were not dose-dependent. Favorable exposure, tolerability, safety, and an extended MRT0-t suggest that WX-081 holds promise as a phase II development candidate for drug-resistant TB treatment.
Assuntos
Antituberculosos , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Adulto , Masculino , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Antituberculosos/sangue , Adulto Jovem , Feminino , Relação Dose-Resposta a Droga , Pessoa de Meia-Idade , Área Sob a Curva , Meia-Vida , China , Povo Asiático , Estudos Cross-Over , População do Leste AsiáticoRESUMO
BACKGROUND: In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. OBJECTIVES: To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. METHODS: We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. RESULTS: The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27-48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. CONCLUSION: No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial.
Assuntos
Antituberculosos , Rifampina , Humanos , Masculino , Adulto , Feminino , Antituberculosos/farmacocinética , África do Sul , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/farmacocinética , Isoniazida/farmacocinética , Consumo de Bebidas Alcoólicas/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias , Pirazinamida/farmacocinética , Pirazinamida/administração & dosagem , Etambutol/farmacocinética , Adulto JovemRESUMO
Inhalable microparticle-based anti TB drug delivery systems are being investigated extensively for Tuberculosis [TB] treatment as they offer efficient and deep lung deposition with several advantages over conventional routes. It can reduce the drug dose, treatment duration and toxic effects and optimize the drug bioavailability. Yeast derived ß-glucan is a ß-[1-3/1-6] linked biocompatible polymer and used as carrier for various biomolecules. Due to presence of glucan chains, particulate glucans act as PAMP and thereby gets internalized via receptor mediated phagocytosis by the macrophages. In this study, ß-glucan microparticles were prepared by adding l-leucine as excipient, and exhibited 70% drug [Rifabutin] loading efficiency. Further, the sizing and SEM data of particles revealed a size of 2-4 µm with spherical dimensions. The FTIR and HPLC data confirmed the ß-glucan composition and drug encapsulations efficiency of the particles. The mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD] data indicated that these particles are inhalable in nature and have better thermal stability as per DSC thermogram. These particles were found to be non-toxic upto a concentration of 80 µg/ml and were found to be readily phagocytosed by human macrophage cells in-vitro as well as in-vivo by lung alveolar macrophage. This study provides a framework for future design of inhalable ß-glucan particle based host-directed drug delivery system against pulmonary TB.
Assuntos
Sistemas de Liberação de Medicamentos , Rifabutina , beta-Glucanas , Rifabutina/administração & dosagem , Rifabutina/farmacocinética , Rifabutina/química , beta-Glucanas/química , Humanos , Administração por Inalação , Tuberculose Pulmonar/tratamento farmacológico , Tamanho da Partícula , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Portadores de Fármacos/química , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/químicaRESUMO
Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 µM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.
Assuntos
Antituberculosos , Autofagia , Mycobacterium tuberculosis , Proteína Fosfatase 2C , Autofagia/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Camundongos , Humanos , Proteína Fosfatase 2C/metabolismo , Proteína Fosfatase 2C/antagonistas & inibidores , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , FemininoRESUMO
BACKGROUND: Insufficient exposure and poor compliance with anti-tuberculosis (TB) medications are risk factors for treatment failure and the development of drug resistance. Measurement of drugs in biological samples, such as blood and saliva, can be used to assess adherence and make dose adjustments by therapeutic drug monitoring (TDM). Finger sweat testing is a convenient and non-invasive method to monitor patients. OBJECTIVES: To assess the feasibility of finger sweat testing for medication adherence and as a semi-quantitative tool for TDM analysis. METHODS: Ten patients provided finger sweat, blood and saliva samples following a controlled dose of isoniazid. Samples were analysed by liquid chromatography-mass spectrometry. RESULTS: Isoniazid can be detected in finger sweat 1-6 h following administration at typically prescribed dosages. The normalisation of isoniazid to creatinine increases the correlation between finger sweat and serum isoniazid concentration and provides a means to account for inconsistent sample volumes. CONCLUSION: We describe the time-course measurement of isoniazid (or drug-to-creatinine ratio) in finger sweat compared to the pharmacokinetic profile in blood for the first time. This technique, adaptable for other drugs, could reduce the burden on clinics and improve patient experience.
Assuntos
Antituberculosos , Creatinina , Monitoramento de Medicamentos , Isoniazida , Suor , Tuberculose , Humanos , Isoniazida/farmacocinética , Isoniazida/administração & dosagem , Suor/química , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Creatinina/sangue , Monitoramento de Medicamentos/métodos , Masculino , Feminino , Adulto , Tuberculose/tratamento farmacológico , Pessoa de Meia-Idade , Cromatografia Líquida/métodos , Espectrometria de Massas , Adesão à Medicação , Adulto Jovem , Saliva/químicaRESUMO
Delivering novel antimycobacterial agents through the pulmonary route using nanoparticle-based systems shows promise for treating diseases like tuberculosis. However, creating dry powder inhaler (DPI) with suitable aerodynamic characteristics while preserving nanostructure integrity and maintaining bioactivity until the active ingredient travels deeply into the lungs is a difficult challenge. We developed DPI formulations containing levofloxacin-loaded solid lipid nanoparticles (SLNs) via spray-drying technique with tailored aerosolization characteristics for effective inhalation therapy. A range of biophysical techniques, including transmission electron microscopy, confocal microscopy, and scanning electron microscopy were used to measure the morphologies and sizes of the spray-dried microparticles that explored both the geometric and aerodynamic properties. Spray drying substantially reduced the particle sizes of the SLNs while preserving their nanostructural integrity and enhancing aerosol dispersion with efficient mucus penetration. Despite a slower uptake rate compared to plain SLNs, the polyethylene glycol modified formulations exhibited enhanced cellular uptake in both A549 and NR8383 cell lines. The percent viability of Mycobacterium bovis had dropped to nearly 0 % by day 5 for both types of SLNs. Interestingly, the levofloxacin-loaded SLNs demonstrated a lower minimum bactericidal concentration (0.25 µg/mL) compared with pure levofloxacin (1 µg/mL), which indicated the formulations have potential as effective treatments for tuberculosis.
Assuntos
Antituberculosos , Inaladores de Pó Seco , Levofloxacino , Nanopartículas , Tamanho da Partícula , Tuberculose , Levofloxacino/administração & dosagem , Levofloxacino/química , Levofloxacino/farmacologia , Nanopartículas/química , Administração por Inalação , Humanos , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológico , Lipídeos/química , Mycobacterium bovis/efeitos dos fármacos , Linhagem Celular , Aerossóis , Células A549 , Animais , Secagem por Atomização , Testes de Sensibilidade Microbiana , Portadores de Fármacos/química , Polietilenoglicóis/química , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacologia , LipossomosRESUMO
BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS: We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 hâ mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.