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1.
Eur Respir J ; 58(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33542052

RESUMO

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.


Assuntos
Antibióticos Antituberculose , Tuberculose , Antituberculosos/uso terapêutico , Humanos , Isoniazida , Pirazinamida , Rifampina , Tuberculose/tratamento farmacológico
2.
J Antimicrob Chemother ; 76(3): 582-586, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33374006

RESUMO

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


Assuntos
Antibióticos Antituberculose , Preparações Farmacêuticas , Tuberculose Pulmonar , Tuberculose , Adulto , Antibióticos Antituberculose/uso terapêutico , Antituberculosos/uso terapêutico , Hidrolases de Éster Carboxílico/genética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Polimorfismo de Nucleotídeo Único , Rifampina/análogos & derivados , Tuberculose/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico
3.
Antimicrob Agents Chemother ; 58(11): 6747-57, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25182637

RESUMO

The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The analyte was stable on the cards for 11 weeks with a desiccant at room temperature and protected from light. The method concordance for paired plasma and whole-blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in acceptable correlation between plasma and whole-blood DBS (Passing-Bablok regression corrected for hematocrit; y = 0.98x + 356). Concentrations of rifapentine may be determined from whole-blood DBS collected via venipuncture after normalization in order to account for the dilutional effects of red blood cells. Additional studies are focused on the application of this methodology to capillary blood collected by finger stick. The simplicity of processing, storage, shipping, and low blood volume makes whole-blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.


Assuntos
Antituberculosos/sangue , Antituberculosos/farmacocinética , Teste em Amostras de Sangue Seco/métodos , Rifampina/análogos & derivados , Cromatografia Líquida , Monitoramento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Estudos Prospectivos , Reprodutibilidade dos Testes , Rifampina/sangue , Rifampina/farmacocinética , Espectrometria de Massas em Tandem , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
4.
Antimicrob Agents Chemother ; 58(6): 3035-42, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24614383

RESUMO

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h(-1), respectively, after a single dose to 2.2 and 5.0 liters · h(-1), respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.).


Assuntos
Antibióticos Antituberculose/farmacocinética , Rifampina/análogos & derivados , Tuberculose/tratamento farmacológico , Adulto , Disponibilidade Biológica , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Rifampina/farmacocinética , Fatores de Tempo , Adulto Jovem
5.
N Engl J Med ; 365(23): 2155-66, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-22150035

RESUMO

BACKGROUND: Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS: We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS: In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS: The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).


Assuntos
Antituberculosos/administração & dosagem , Isoniazida/administração & dosagem , Rifampina/análogos & derivados , Tuberculose/prevenção & controle , Adulto , Antituberculosos/efeitos adversos , Terapia Diretamente Observada , Esquema de Medicação , Quimioterapia Combinada , Seguimentos , Humanos , Análise de Intenção de Tratamento , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Fatores de Risco , Autoadministração , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Latência Viral
6.
Am J Respir Crit Care Med ; 184(8): 972-9, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21737585

RESUMO

The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation ofa specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation.


Assuntos
Biomarcadores/análise , Ensaios Clínicos como Assunto/normas , Manejo de Espécimes/normas , Tuberculose , Antituberculosos/uso terapêutico , Bancos de Espécimes Biológicos , Biomarcadores/metabolismo , Humanos , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/metabolismo
7.
Antimicrob Agents Chemother ; 54(10): 4192-200, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20660695

RESUMO

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC(0-24)] of 40.2 versus 40.9 µg.h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC(0-24) was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC(0-24) was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC(0-24) was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 µg.h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC(0-24) values was observed, but the mean values of the AUC(0-24) did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.


Assuntos
Antibióticos Antituberculose/farmacocinética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único/genética , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , África , Antibióticos Antituberculose/uso terapêutico , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Análise Multivariada , América do Norte , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Rifampina/uso terapêutico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Espanha , Adulto Jovem
8.
Tuberculosis (Edinb) ; 94(3): 187-96, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24629635

RESUMO

BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.


Assuntos
Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Biomarcadores/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteômica/métodos , Técnica de Seleção de Aptâmeros/métodos , Resultado do Tratamento , Tuberculose Pulmonar/sangue , Adulto Jovem
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