RESUMO
OBJECTIVE: To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM). DESIGN: Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis. SETTING: Hasan Sadikin Hospital, Bandung, Indonesia. PATIENTS: Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines. INTERVENTIONS: Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment. MAIN OUTCOME MEASURES: Plasma exposures during the daily dosing interval (AUC0-24), peak plasma concentrations (Cmax) and CSF concentrations. RESULTS: Among 20 eligible patients, geometric mean AUC0-24 of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hourâmg/L on day 2; and 14.5, 71.8 and 328.4 hourâmg/L on day 10, respectively. Large interindividual variabilities were observed in AUC0-24 and Cmax of all drugs. All patients had suboptimal rifampicin AUC0-24 for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC0-24 of isoniazid, rifampicin and pyrazinamide along with Cmax of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05). CONCLUSION: Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
Assuntos
Isoniazida/farmacocinética , Pirazinamida/farmacocinética , Rifampina/farmacocinética , Tuberculose Meníngea/tratamento farmacológico , Adolescente , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Área Sob a Curva , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Indonésia , Lactente , Recém-Nascido , Isoniazida/sangue , Isoniazida/líquido cefalorraquidiano , Isoniazida/uso terapêutico , Masculino , Estudos Prospectivos , Pirazinamida/sangue , Pirazinamida/líquido cefalorraquidiano , Pirazinamida/uso terapêutico , Rifampina/sangue , Rifampina/líquido cefalorraquidiano , Rifampina/uso terapêuticoRESUMO
The pharmacokinetic profiling of drug substances and corresponding metabolites in the biological matrix is one of the most informative tools for the treatment efficacy assessment. Therefore, to satisfy the need for comprehensive monitoring of anti-tuberculosis drugs in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of first-line anti-tuberculosis drugs (ethambutol, isoniazid, pyrazinamide, and rifampicin) along with their six primary metabolites. Simple single-step protein precipitation with methanol was chosen as the most convenient sample pre-treatment method. Chromatographic separation of the ten analyte mixture was achieved within 10 minutes on a reverse-phase C8 column using mobile phase gradient mode. The multiple reaction monitoring mode (MRM) was used for analyte detection and quantification in patient samples. The chosen quantification ranges fully covered expected plasma concentrations. The method exhibited acceptable selectivity; the within- and between-run accuracy ranged from 87.2 to 113.6%, but within- and between-run precision was between 1.6 and 14.9% (at the LLOQ level CV < 20%). Although the response of the isonicotinic acid varied depending on the matrix source (CV 21.8%), validation results proved that such inconsistency does not affect the accuracy and precision of results. If stored at room temperature plasma samples should be processed within 4 h after collection, temporary storage at -20 °C up to 24 h is acceptable due to stability issues of analytes. The developed method was applied for the patient sample analysis (n = 34) receiving anti-tuberculosis treatment with the first-line drugs.
Assuntos
Antituberculosos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Tuberculose/tratamento farmacológico , Antituberculosos/sangue , Antituberculosos/uso terapêutico , Monitoramento de Medicamentos/instrumentação , Etambutol/sangue , Etambutol/farmacocinética , Etambutol/uso terapêutico , Humanos , Isoniazida/sangue , Isoniazida/farmacocinética , Isoniazida/uso terapêutico , Plasma/química , Pirazinamida/sangue , Pirazinamida/farmacocinética , Pirazinamida/uso terapêutico , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/uso terapêutico , Tuberculose/sangueRESUMO
The aim of this study was to establish and validate an alternative high-performance liquid chromatography method for simultaneous quantification of pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin in plasma of patients under treatment for tuberculosis. The performed method was lineal (r2 > 0.99) in the range of 2.00-50.00 µg/mL for pyrazinamide, 0.50-20.00 µg/mL for both acetyl-isoniazid and isoniazid, and 1.20-25.00 µg/mL for rifampicin. Precision and trueness were demonstrated with coefficient of variation < 15% and deviations < 15%, respectively, for quality controls samples. The lower limits of quantification were 2.00, 0.50, 0.50, and 1.20 µg/mL for pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin, respectively. The method was applied for the analysis of plasma from patients with tuberculosis. This method allowed ensuring reliable quantification of the target compounds and their pharmacokinetics parameters. In general, the mean values of maximum concentration of each antituberculosis drug were located within their respective reference therapeutic ranges. However, patients with sub-therapeutic plasma concentrations of isoniazid and rifampicin were detected. This is the first analytical technique that simultaneously quantifies isoniazid, acetyl-isoniazid, rifampicin, and pyrazinamide concentrations from plasma samples by high-performance liquid chromatography with ultraviolet/visible. The proposed method could be applied for therapeutic drug monitoring and pharmacokinetics studies of the four compounds throughout the treatment of tuberculosis patients.
Assuntos
Isoniazida/sangue , Pirazinamida/sangue , Rifampina/sangue , Tuberculose/sangue , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Controle de Qualidade , Tuberculose/diagnósticoRESUMO
We aimed to investigate the effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti- tuberculosis (TB) drugs in Chinese population. Newly diagnosed TB patients administered the anti-TB drugs under fasting conditions orally, and then had prepared breakfast at 30âminutes and 120âmin after dosing, respectively. Blood sampling was also performed 120â minutes after dosing for the detection of Cmax purpose. Overall, twenty-five participants were included in our analysis. The Cmaxs of 30â minutes interval and 120â minutes interval were 21.8â±â2.0 and 19.2â±â2.0âµg/mL for rifampin, 1.6â±â0.2 and 2.1â±â0.2âµg/mL for isoniazid (INH), 1.5â±â0.1and 1.5â±â0.2âµg/mL for ethambutol (EMB), and 49.2â±â3.7 and 41.5â±â3.9âµg/mL for pyrazinamide, respectively. Statistical analysis revealed that there was no statistical difference between 2 groups. Additionally, 88.0% and 72.0% of the 25 participants at 2-hour interval group had peak concentrations less than the lower limit of the reference range for INH and EMB, respectively. The Cmaxs of INH were 0.9â±â0.4âµg/ml for rapid acetylator, which was significantly lower than those of intermediate (1.4â±â1.0âµg/mL), and slow acetylator (2.5â±â1.0âµg/mL), respectively (Pâ<â.01). In conclusion, our data demonstrate that early food intake at 30âminutes after drug administration had no significant influence on the plasma concentrations. In addition, a high proportion of patients receiving first-line anti-TB regimen fail to achieve the expected plasma drug ranges of INH and EMB (Pâ>â.05).
Assuntos
Antituberculosos/sangue , Ingestão de Alimentos , Jejum/sangue , Fatores de Tempo , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Administração Oral , Adulto , Antituberculosos/administração & dosagem , China , Esquema de Medicação , Etambutol/administração & dosagem , Etambutol/sangue , Feminino , Humanos , Isoniazida/administração & dosagem , Isoniazida/sangue , Masculino , Pirazinamida/administração & dosagem , Pirazinamida/sangue , Rifampina/administração & dosagem , Rifampina/sangue , Resultado do TratamentoRESUMO
Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging due to high treatment failure rate and adverse drug events. This study aimed to develop and validate a simple LC-MS/MS method for simultaneous measurement of five TB drugs in human plasma and to facilitate therapeutic drug monitoring (TDM) in MDR-TB treatment to increase efficacy and reduce toxicity. Moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were prepared in blank plasma from healthy volunteers and extracted using protein precipitation reagent containing trichloroacetic acid. Separation was achieved on an Atlantis T3 column with gradient of 0.1% formic acid in water and acetonitrile. Drug concentrations were determined by dynamic multiple reaction monitoring in positive ion mode on a LC-MS/MS system. The method was validated according to the United States' Food and Drug Administration (FDA) guideline for bioanalytical method validation. The calibration curves for moxifloxacin, levofloxacin, prothionamide, pyrazinamide and ethambutol were linear, with the correlation coefficient values above 0.993, over a range of 0.1-5, 0.4-40, 0.2-10, 2-100 and 0.2-10 mg/L, respectively. Validation showed the method to be accurate and precise with bias from 6.5% to 18.3% for lower limit of quantification and -5.8% to 14.6% for LOW, medium (MED) and HIGH drug levels, and with coefficient of variations within 11.4% for all levels. Regarding dilution integrity, the bias was within 7.2% and the coefficient of variation was within 14.9%. Matrix effect (95.7%-112.5%) and recovery (91.4%-109.7%) for all drugs could be well compensated by their isotope-labelled internal standards. A benchtop stability test showed that the degradation of prothionamide was over 15% after placement at room temperature for 72 h. Clinical samples (n = 224) from a cohort study were analyzed and all concentrations were within the analytical range. The signal of prothionamide was suppressed in samples with hemolysis which was solved by sample dilution. As the method is robust and sample preparation is simple, it can easily be implemented to facilitate TDM in programmatic MDR-TB treatment.
Assuntos
Cromatografia Líquida/métodos , Etambutol/sangue , Fluoroquinolonas/sangue , Protionamida/sangue , Pirazinamida/sangue , Adulto , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
In this research, we developed and validated a liquid chromatography coupled to mass spectrometry (LC-QToF-MS) method for simultaneous quantification of the anti-tuberculosis drugs ethambutol, isoniazid, pyrazinamide and rifampicin in human plasma. Plasma samples spiked with cimetidine (internal standard) were extracted using protein precipitation with acetonitrile containing 1% formic acid. Separation was performed using a C18 column under flow gradient conditions with water and acetonitrile, both containing 5 mm ammonium formate and 0.1% formic acid. The method was validated according to the ANVISA and US Food and Drug Administration guidelines for bioanalytical method validation. The calibration curve was linear over a concentration range of 0.2-5 µg ml-1 for ethambutol, 0.2-7.5 µg ml-1 for isoniazid, 1-40 µg ml-1 for pyrazinamide and 0.25-2 µg ml-1 for rifampicin, all with adequate precision and accuracy. The method was reproducible, selective and free of carryover and matrix effects. The validated LC-QToF-MS method was successfully applied to real samples and shown to be applicable to future therapeutic and pharmacokinetic monitoring studies.
Assuntos
Antituberculosos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Etambutol/sangue , Isoniazida/sangue , Espectrometria de Massas/métodos , Pirazinamida/sangue , Rifampina/sangue , Humanos , Plasma/químicaRESUMO
With the increased cases of multidrug- or rifampicin-resistant tuberculosis and co-infection with HIV globally, it is difficult to achieve ideal clinical responses because of poor drug absorption and drug-drug interactions. Herein, a bioanalytical UPLC-MS/MS method was developed and validated to quantify five anti-TB agents in human plasma samples for detecting blood drug concentrations to improve therapeutic effects. To overcome the matrix effects, stable isotope labeled analogue of each analyte was used for internal standardization. A simple single-step protein precipitation by acetonitrile was employed for the sample preparation, then the analytes including rifampicin, rifabutin, pyrazinamid, ethambutol, isoniazid and their isotope labeled internal standards (ILISs) were implemented on an HILIC silica column with a gradient mode. The linear range for each analyte was covering the peak drug concentration (Cmax) in the 20 times diluted plasma samples. The coefficient of variation of intra- and inter-day precision was less than 17.0 %, and the accuracy ranged between 91.5 and 110.0 %. The extraction recoveries of all agents were ≥90.2 %, and the matrix effects with internal standard-normalization for all agents were 97.1-110.0 %. The optimal blood sampling time was designed basing on the results of stability validation. This UPLC-MS/MS method with a run time of 3.5â¯min was successfully applied to routine therapeutic monitoring of the five anti-TB agents in patient plasma.
Assuntos
Antituberculosos/sangue , Monitoramento de Medicamentos/métodos , Etambutol/sangue , Isoniazida/sangue , Pirazinamida/sangue , Rifabutina/sangue , Rifampina/sangue , Infecções Oportunistas Relacionadas com a AIDS/sangue , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/instrumentação , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Tuberculose/sangueRESUMO
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.
Assuntos
Antituberculosos/sangue , Antituberculosos/farmacocinética , Complicações do Diabetes , Diabetes Mellitus/sangue , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Diabetes Mellitus/microbiologia , Feminino , Humanos , Isoniazida/sangue , Isoniazida/farmacocinética , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Plasma , Estudos Prospectivos , Pirazinamida/sangue , Pirazinamida/farmacocinética , Pirazinamida/uso terapêutico , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/uso terapêutico , Tanzânia , Resultado do Tratamento , Adulto JovemRESUMO
Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the determinants of serum concentration need further evidences.In a retrospective case-control study, clinical and laboratory data were collected from 717 in-patients with TB at Xi'an Chest Hospital, China. Two hours serum concentrations of isoniazid, rifampicin, pyrazinamide as well as ethambutol were obtained and analyzed by liquid chromatography-tandem mass spectrometry.The month 2 culture conversion group had lower concentration of isoniazid, pyrazinamide, and ethambutol than month 1 group. Statistical analysis showed that serum concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol revealed a positive relationship with dose (mg/kg) (Pâ<â.001, Pâ<â.001, Pâ<â.001, and Pâ=â.003, respectively). Furthermore, isoniazid concentration was related to smoking (Pâ=â.009) and prior TB (Pâ=â.011), while rifampicin and pyrazinamide concentrations were correlated to sex (Pâ=â.004 and 0.025, respectively). Ethambutol concentration was associated with creatinine clearance (Ccr, Pâ=â.002).It is necessary to optimize drug doses using therapeutic drug monitoring while considering the following determinants: weight, smoking status, prior TB, sex, and Ccr. Furthermore, low 2âhours serum concentrations can be associated with longer culture conversion.
Assuntos
Etambutol/sangue , Isoniazida/sangue , Pirazinamida/sangue , Rifampina/sangue , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/sangue , Antituberculosos/metabolismo , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , China/epidemiologia , Cromatografia Líquida/instrumentação , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Etambutol/metabolismo , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/metabolismo , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazinamida/metabolismo , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/metabolismo , Rifampina/uso terapêutico , Fatores Sexuais , Fumar/efeitos adversos , Tuberculose/sangue , Adulto JovemRESUMO
Herein, we report a novel composite fabricated via embedding rod-like Co based metal-organic framework (Co-MOF-74) crystals into MC matrix for the first time. The introduction of MC astricts the size of Co-MOF-74 crystals, enlarges the pore size and improves the electrical conductivity, which lead to the good electrochemical properties of the composite. The fabricated sensor based on Co-MOF-74@MC exhibits superior electrocatalytic activity toward the reduction of pyrazinamide (PZA) and the oxidation of isonicotinyl hydrazide (INZ). Under optimized conditions, the sensor shows two linear ranges from 0.3 to 46.5⯵M and 46.5-166.5⯵M with a high sensitivity of 7.2⯵A⯵M-1â¯cm-2 and a detection limit of 0.21⯵M for the determination of PZA. The electroanalytical sensing of INZ also gives two linear ranges of 0.15-1.55⯵M and 1.55-592.55⯵M with a detection limit of 0.094⯵M. The mechanism involved was also discussed, briefly. The sensor is assessed toward the detection of PZA and INZ in human serum and urine samples. Recovery values varied from 97.08 to 103.20% for PZA sensing and 96.67-102.90% for INZ sensing, revealing the promising practicality of sensor for PZA and INZ detection.
Assuntos
Análise Química do Sangue/métodos , Carbono/química , Cobalto/química , Vidro/química , Isoniazida/análise , Estruturas Metalorgânicas/química , Pirazinamida/análise , Urinálise/métodos , Análise Química do Sangue/instrumentação , Catálise , Eletroquímica , Eletrodos , Humanos , Isoniazida/sangue , Isoniazida/química , Isoniazida/urina , Limite de Detecção , Oxirredução , Porosidade , Pirazinamida/sangue , Pirazinamida/química , Pirazinamida/urina , Urinálise/instrumentaçãoRESUMO
Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.
Assuntos
Antituberculosos/farmacocinética , Diarilquinolinas/farmacocinética , Linezolida/farmacocinética , Síndrome do QT Longo/induzido quimicamente , Modelos Estatísticos , Nitroimidazóis/farmacocinética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/efeitos adversos , Antituberculosos/sangue , Simulação por Computador , Diarilquinolinas/efeitos adversos , Diarilquinolinas/sangue , Método Duplo-Cego , Quimioterapia Combinada/métodos , Eletrocardiografia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Linezolida/efeitos adversos , Linezolida/sangue , Síndrome do QT Longo/sangue , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Moxifloxacina/efeitos adversos , Moxifloxacina/sangue , Moxifloxacina/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Nitroimidazóis/efeitos adversos , Nitroimidazóis/sangue , Pirazinamida/efeitos adversos , Pirazinamida/sangue , Pirazinamida/farmacocinética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/patologiaRESUMO
BACKGROUND: The 24-h area under the concentration-time curve (AUC24)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC24; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs. METHODS: An OSS for the prediction of AUC24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment. RESULTS: OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS2-4-8 cannot be used for rifampicin in steady state conditions. CONCLUSION: OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC24 values of first-line anti-TB drugs in this population. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02121314).
Assuntos
Antituberculosos/farmacocinética , Monitoramento de Medicamentos/métodos , Tuberculose/sangue , Adulto , Antituberculosos/sangue , Estudos Cross-Over , Etambutol/sangue , Etambutol/farmacocinética , Jejum/metabolismo , Feminino , Humanos , Isoniazida/sangue , Isoniazida/farmacocinética , Masculino , Pessoa de Meia-Idade , Pirazinamida/sangue , Pirazinamida/farmacocinética , Rifampina/sangue , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Adulto JovemAssuntos
Antituberculosos/sangue , Pirazinamida/sangue , Tuberculose Pulmonar/sangue , Antituberculosos/administração & dosagem , Brasil , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/administração & dosagem , Fatores Sexuais , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Determining the optimal dosages of isoniazid, rifampicin, pyrazinamide and ethambutol in children is necessary to obtain therapeutic serum concentrations of these drugs. Revised dosages have improved the exposure of 1st line anti-tubercular drugs to some extent; there is still scope for modification of the dosages to achieve exposures which can lead to favourable outcome of the disease. High dose of rifampicin is being investigated in clinical trials in adults with some benefit; studies are required in children. Inter-individual pharmacokinetic variability and the effect of age, nutritional status, Human immunodeficiency virus (HIV) infection, acetylator genotype may need to be accounted for in striving for the dosages best suited for an individual.
Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológico , Fatores Etários , Antituberculosos/sangue , Antituberculosos/uso terapêutico , Criança , Overdose de Drogas , Etambutol/administração & dosagem , Etambutol/sangue , Alimentos , Genótipo , Infecções por HIV/complicações , Humanos , Isoniazida/administração & dosagem , Isoniazida/sangue , Desnutrição/complicações , Estado Nutricional , Polimorfismo Genético , Pirazinamida/administração & dosagem , Pirazinamida/sangue , Rifampina/administração & dosagem , Rifampina/sangue , Resultado do TratamentoAssuntos
Humanos , Masculino , Feminino , Pirazinamida/sangue , Tuberculose Pulmonar/sangue , Antituberculosos/sangue , Pirazinamida/administração & dosagem , Fatores de Tempo , Tuberculose Pulmonar/tratamento farmacológico , Brasil , Fatores Sexuais , Resultado do Tratamento , Estatísticas não Paramétricas , Relação Dose-Resposta a Droga , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/administração & dosagemRESUMO
BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0-24h were calculated. RESULTS: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. CONCLUSION: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.
Assuntos
Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Adolescente , Antituberculosos/sangue , Criança , Pré-Escolar , Etambutol/sangue , Etambutol/farmacocinética , Etambutol/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Pirazinamida/sangue , Pirazinamida/farmacocinética , Pirazinamida/uso terapêutico , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/uso terapêutico , Tuberculose/tratamento farmacológicoRESUMO
OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines. INTERVENTIONS: Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations. MAIN OUTCOME MEASURE: The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time -concentration curve (AUC0-8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables. RESULTS: For INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0-8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0-8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0-8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0-8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0-8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0-8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0-8 hours 208.77 µg/mL hour, P=0.01). CONCLUSIONS: The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.
Assuntos
Antituberculosos/farmacocinética , Isoniazida/farmacocinética , Pirazinamida/farmacocinética , Tuberculose/tratamento farmacológico , Adolescente , Fatores Etários , Antituberculosos/sangue , Antituberculosos/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Lactente , Isoniazida/sangue , Isoniazida/uso terapêutico , Masculino , Desnutrição/complicações , Análise Multivariada , Estado Nutricional , Guias de Prática Clínica como Assunto , Pirazinamida/sangue , Pirazinamida/uso terapêutico , Resultado do Tratamento , Tuberculose/sangue , Tuberculose/complicaçõesRESUMO
First-line anti-tuberculosis drugs are playing vital roles for curbing rapid spread of tuberculosis. Multidrug therapies are commonly applied in clinical to achieve better treatment outcomes. However, drug resistance and adverse reactions come along with this therapies and therapeutic drug monitoring is a feasible way to precaution them. For this reasons, a simple and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and single protein precipitation was developed and validated for simultaneously quantifying of pyrazinamide, isoniazid, ethambutol, streptomycin and rifampicin in human plasma. Optimized chromatographic separation was achieved on a ZORBAX SB-C18 column with heptafluorobutyric acid, an ion-pair reagent, in the mobile phase at a flow rate of 0.3 mL/min. The mass detection was achieved using electrospray ionization in the positive ion mode with a multiple reaction monitoring mode. The lower limit of quantification (LLOQ) and dynamic range of pyrazinamide, isoniazid, ethambutol, streptomycin and rifampicin were 200-4000 ng/mL, 80-2000 ng/mL, 0.2-1000 ng/mL, 2000-200000 ng/mL and 200-4000 ng/mL, respectively. The Inter-day and intra-day accuracy and precision were within ±15.0% and less than 15%. The method had been successfully applied to simultaneous determination of four first-line Anti-tuberculosis drugs in plasma from tuberculosis patients.
Assuntos
Antituberculosos/sangue , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos/métodos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Tuberculose/sangue , Antituberculosos/uso terapêutico , Etambutol/sangue , Humanos , Isoniazida/sangue , Valor Preditivo dos Testes , Pirazinamida/sangue , Reprodutibilidade dos Testes , Rifampina/sangue , Estreptomicina/sangue , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologiaRESUMO
Pyrazinamide (PYZ)-an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis-is well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg-1 for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.
Assuntos
Antituberculosos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Metabolômica/métodos , Pirazinamida/análogos & derivados , Pirazinamida/toxicidade , Testes de Toxicidade/métodos , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/sangue , Biomarcadores/sangue , Biotransformação , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/metabolismo , Fígado/ultraestrutura , Masculino , Microscopia Eletrônica de Varredura , Análise Multivariada , Estresse Oxidativo/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Pirazinamida/administração & dosagem , Pirazinamida/sangue , Ratos Wistar , Medição de Risco , Fatores de TempoRESUMO
Studies have demonstrated the efficacy of pyrazinamide (PZA) against stages of the Leishmania parasite that causes cutaneous leishmaniasis. Although PZA is widely distributed in most body fluids and tissues, the amount of drug reaching the skin is unknown. This study aimed to investigate the pharmacokinetics of PZA in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics was assessed by implanting a linear microdialysis probe in the dermis of ten rats. In addition, blood samples were collected to assess plasma pharmacokinetics. Unbound microdialysate (N = 280) and plasma (N = 120) concentrations following single intravenous doses of 25 mg/kg or 50 mg/kg PZA were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. Non-compartmental analysis and non-linear mixed-effects modelling were performed using WinNonlin and NONMEM v.7.3. PZA rapidly permeated into the dermis and reached high levels, with mean maximum concentrations (Cmax) of 22.4 ± 7.1 µg/mL and 48.6 ± 17.3 µg/mL for the two doses studied. PZA showed significant distribution to the skin (fAUCdermal/fAUCplasma = 0.82 ± 0.31 and 0.84 ± 0.25 for 25 mg/kg and 50 mg/kg doses, respectively). Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that free PZA levels in plasma were in equilibrium with tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. This study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.