RESUMEN
Rifampicin is a frontline antibiotic in the management of tuberculosis. Since no spectrofluorimetric methods are reported for this drug, this approach was challenged to craft a sensitive, reliable, valid, fast, and green methodology. In recent years, fluorescence spectroscopy has received a lot of interest. Its benefits include ecological greenness and analytical performance. The pharmaceutical industries greatly like this approach because of its low energy and decreased solvent usage, which make it both economical and environmentally friendly. This methodology was based on utilizing the enhanced native fluorescence of the rifampicin at 341 nm after excitation at 241 nm in a beta-cyclodextrin micellar system. Modern developments in analytical chemistry have been applied to reduce risks to the workplace and environment by using distilled water as a dilution solvent for method application and optimization. The method was found excellent green with 97 eco-scale and 0.86 AGREE scores besides an 89.6 overall whiteness score. The range of linearity for rifampicin raw material was 0.2-1.5 µg·mL-1, and the average recoveries for raw material and spiked plasma were 100.15% and 99.64%, respectively. The suggested technique worked well for the commercial oral syrup of Rimactane® and did not conflict with any common additives.
Asunto(s)
Micelas , Rifampin , Espectrometría de Fluorescencia , Agua , Rifampin/análisis , Rifampin/sangre , Rifampin/química , Agua/química , beta-Ciclodextrinas/química , Antituberculosos/análisis , Antituberculosos/química , Antibióticos Antituberculosos/análisis , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/químicaRESUMEN
Abstract Rifampicin is a key component of treatment for tuberculosis and its efficacy is determined by the blood levels attained after therapeutic doses. However, there is a high variability of rifampicin blood levels that is related to both the patient and the formulation used. To date, the effect of diabetes mellitus on the plasma levels of rifampicin was low exploited, which could be relevant either by the significant increase of the comorbidity worldwide as by the probable influence of diabetes on the rifampicin exposure. The study aims to evaluate whether diabetes mellitus contribute to the variation of the maximum concentration of rifampicin in patients with tuberculosis treated with a daily dose of 10 mg/kg. Rifampicin and glycated hemoglobin were measured by high-performance liquid chromatography, and blood glucose by spectrophotometry. A total of 62 male patients were included in the study, and 26 presented diabetes mellitus. Rifampicin plasma levels in 2-h plasma samples collected at day 61 ranged from 3 µg/mL to 14.2 µg/mL. Drugs levels were similar between diabetic and non-diabetic patients and were not correlated with blood glucose and glycated hemoglobin. Moreover, a high percentage of patients in both groups presented low levels of rifampicin.
Asunto(s)
Humanos , Masculino , Rifampin/sangre , Tuberculosis/sangre , Diabetes Mellitus/sangre , Antibióticos Antituberculosos/sangre , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Glucemia , Cromatografía Líquida de Alta Presión , Antibióticos Antituberculosos/uso terapéuticoRESUMEN
Rifampicin is a key component of treatment for tuberculosis and its efficacy is determined by the blood levels attained after therapeutic doses. However, there is a high variability of rifampicin blood levels that is related to both the patient and the formulation used. To date, the effect of diabetes mellitus on the plasma levels of rifampicin was low exploited, which could be relevant either by the significant increase of the comorbidity worldwide as by the probable influence of diabetes on the rifampicin exposure. The study aims to evaluate whether diabetes mellitus contribute to the variation of the maximum concentration of rifampicin in patients with tuberculosis treated with a daily dose of 10mg/kg. Rifampicin and glycated hemoglobin were measured by high-performance liquid chromatography, and blood glucose by spectrophotometry. A total of 62 male patients were included in the study, and 26 presented diabetes mellitus. Rifampicin plasma levels in 2-h plasma samples collected at day 61 ranged from 3µg/mL to 14.2µg/mL. Drugs levels were similar between diabetic and non-diabetic patients and were not correlated with blood glucose and glycated hemoglobin. Moreover, a high percentage of patients in both groups presented low levels of rifampicin.
Asunto(s)
Antibióticos Antituberculosos/sangre , Diabetes Mellitus/sangre , Rifampin/sangre , Tuberculosis/sangre , Antibióticos Antituberculosos/uso terapéutico , Glucemia , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection. METHODS: This is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay. RESULTS: The Cmax and AUC0-12h medians in arm A (Cmax = 296 ng/mL, IQR: 205-45; AUC0-12h = 2528 ng.h/mL, IQR: 1684-2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403-717; AUC0-12h = 4042.5 ng.h/mL, IQR: 3469-5761), with a statistically significant difference in AUC0-12h (p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm. CONCLUSION: This study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria. TRIAL REGISTRATION: PACTR201310000629390, 28th October 2013.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/uso terapéutico , Coinfección/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Lopinavir/uso terapéutico , Rifabutina/administración & dosificación , Rifabutina/uso terapéutico , Ritonavir/uso terapéutico , Tuberculosis/tratamiento farmacológico , Adulto , Antibióticos Antituberculosos/efectos adversos , Antibióticos Antituberculosos/sangre , Burkina Faso , Cromatografía Líquida de Alta Presión , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Proyectos Piloto , Distribución Aleatoria , Rifabutina/efectos adversos , Rifabutina/sangre , Espectrometría de Masas en TándemRESUMEN
To address the most appropriate endogenous biomarker for drug-drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate-3-glucuronide, glycochenodeoxycholate-3-sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose-dependent change in area under the plasma concentration-time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0-24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR-1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B-mediated drug-drug interaction risk assessment approaches based on agency guidelines in early clinical trials.
Asunto(s)
Interacciones Farmacológicas/fisiología , Transportador 1 de Anión Orgánico Específico del Hígado/sangre , Rifampin/administración & dosificación , Rifampin/sangre , Adulto , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/sangre , Biomarcadores/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , MasculinoRESUMEN
Rifampicin is used in both phases of treatment for tuberculosis. In chronic use, the short half-life and the self-induction of metabolism can decrease the levels of the drug below the minimal inhibitory concentration. The aim of the study was to investigate whether plasma concentrations of rifampicin are sustained above 0.5µg/mL in patients with tuberculosis using 600mg/day. Rifampicin was measured in plasma by high-performance liquid chromatography and a sputum smear microscopy was performed in all days of the study. A total of 44 male patients completed the study. On days 31, 61 and 91, the mean plasma concentrations of rifampicin were 0.6 (0.5)µg/mL, 0.55 (0.5)µg/mL and 0.46 (0.4)µg/mL. There was a high variation of rifampicin levels leading to a high percentage of samples with concentrations below 0.5µg/mL. There was no significant association between the frequency of samples with drug levels below 0.5µg/mL with the conversion of the sputum microscopy. These data suggest that pre-doses samples offer limited information on the exposure of M. tuberculosis to rifampicin.
Asunto(s)
Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/sangre , Rifampin/administración & dosificación , Rifampin/sangre , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los Resultados , Esputo/efectos de los fármacos , Esputo/microbiología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure. METHODS: A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration-time curve to the last observation point (AUC0-24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein-P and OATP1B1) were determined. RESULTS: A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0-24 h of RMP and INH. Results indicated that RMP Cmax and AUC0-24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0-24 h for INH. CONCLUSIONS: Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.
Asunto(s)
Antibióticos Antituberculosos/sangre , Antituberculosos/sangre , Isoniazida/sangre , Rifampin/sangre , Tuberculosis/sangre , Tuberculosis/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adolescente , Adulto , Anciano , Antropometría/métodos , Antibióticos Antituberculosos/uso terapéutico , Antituberculosos/uso terapéutico , Arilamina N-Acetiltransferasa/genética , Cromatografía Líquida de Alta Presión/métodos , Femenino , Genotipo , Humanos , Isoniazida/uso terapéutico , Masculino , México , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Adulto JovenRESUMEN
A simple and sensitive ultra-performance liquid chromatography tandem mass spectrometry method has been developed and validated for the analysis of cycloserine in patients' plasma. Using methanol, cyloserine and propranolol (internal standard (IS)) was extracted from plasma by protein precipitation procedure. The chromatographic separation was successfully achieved on Phenomenex KinetexTM PFP C18 (2.1 mm × 100 mm, 2.6 µm) reversed-phase column. Acidified with 0.1% formic acid, water and acetonitrile were used as mobile phases for gradient elution. Cycloserine and IS were detected by Xevo® TQ MS triple quadrupole tandem mass spectrometer. The transition of protonated precursor to product ion were monitored at 103 â 75 m/z and 260.2 â 183 m/z for cycloserine and IS, respectively. The lower limit of quantification was 0.01 µg/mL. The method was linear over the concentration range 0.01-50 µg/mL with average coefficient of determination of 0.9994. The within-run and between-run precision and accuracy were in the range 3.7-19.3% (RSD) and 98.7-117.3%, respectively. Processed cycloserine sample was stable for 48 hours at 8°C and after three freeze-thaw cycles. The extraction efficiency ranged between 88.7 and 91.2%. The method was successfully applied in a pharmacokinetic study for the determination of cycloserine in plasma of patients with drug-resistant tuberculosis.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cicloserina/sangre , Espectrometría de Masas en Tándem/métodos , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/química , Antibióticos Antituberculosos/farmacocinética , Antibióticos Antituberculosos/uso terapéutico , Cicloserina/química , Cicloserina/farmacocinética , Cicloserina/uso terapéutico , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
ABSTRACT Rifampicin is used in both phases of treatment for tuberculosis. In chronic use, the short half-life and the self-induction of metabolism can decrease the levels of the drug below the minimal inhibitory concentration. The aim of the study was to investigate whether plasma concentrations of rifampicin are sustained above 0.5 µg/mL in patients with tuberculosis using 600 mg/day. Rifampicin was measured in plasma by high-performance liquid chromatography and a sputum smear microscopy was performed in all days of the study. A total of 44 male patients completed the study. On days 31, 61 and 91, the mean plasma concentrations of rifampicin were 0.6 (0.5) µg/mL, 0.55 (0.5) µg/mL and 0.46 (0.4) µg/mL. There was a high variation of rifampicin levels leading to a high percentage of samples with concentrations below 0.5 µg/mL. There was no significant association between the frequency of samples with drug levels below 0.5 µg/mL with the conversion of the sputum microscopy. These data suggest that pre-doses samples offer limited information on the exposure of M. tuberculosis to rifampicin.
Asunto(s)
Humanos , Masculino , Adulto , Persona de Mediana Edad , Adulto Joven , Rifampin/administración & dosificación , Rifampin/sangre , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/sangre , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/sangre , Valores de Referencia , Esputo/efectos de los fármacos , Esputo/microbiología , Pruebas de Sensibilidad Microbiana , Estudios Prospectivos , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión , Resultado del Tratamiento , Relación Dosis-Respuesta a Droga , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
The pharmacokinetic (PK) and clinical implications of combining metformin with rifampicin are relevant to increasing numbers of patients with diabetic tuberculosis (TB) across the world and are yet unclear. We assessed the impact of rifampicin on metformin PKs and its glucose-lowering effect in patients with diabetic TB by measuring plasma metformin and blood glucose during and after TB treatment. Rifampicin increased metformin exposure: plasma area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-τ ) and peak plasma concentration (Cmax ) geometric mean ratio (GMR; during vs. after TB treatment) were 1.28 (90% confidence interval (CI) 1.13-1.44) and 1.19 (90% CI 1.02-1.38; n = 22). The metformin glucose-lowering efficacy did not change (Δglucose - Cmax ; P = 0.890; n = 18). Thus, we conclude that additional glucose monitoring in this population is not warranted. Finally, 57% of patients on metformin and rifampicin, and 38% of patients on metformin alone experienced gastrointestinal adverse effects. Considering this observation, we advise patients to take metformin and rifampicin with food and preferably separated in time. Clinicians could consider metoclopramide if gastrointestinal adverse effects occur.
Asunto(s)
Antibióticos Antituberculosos/sangre , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/sangre , Metformina/sangre , Rifampin/sangre , Tuberculosis/sangre , Adolescente , Adulto , Anciano , Antibióticos Antituberculosos/administración & dosificación , Glucemia/efectos de los fármacos , Estudios de Cohortes , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Interacciones Farmacológicas/fisiología , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Adulto JovenRESUMEN
High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0-24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.).
Asunto(s)
Antibióticos Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin/farmacología , Tuberculosis Meníngea/tratamiento farmacológico , Administración Oral , Adulto , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/líquido cefalorraquídeo , Antibióticos Antituberculosos/farmacocinética , Área Bajo la Curva , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/patogenicidad , Seguridad del Paciente , Rifampin/sangre , Rifampin/líquido cefalorraquídeo , Rifampin/farmacocinética , Análisis de Supervivencia , Tuberculosis Meníngea/microbiología , Tuberculosis Meníngea/mortalidad , Tuberculosis Meníngea/patologíaRESUMEN
BACKGROUND: Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations. METHODS: Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 ≥ 3 mg/l; criterion 2: C3 or C6 ≥ 5 mg/l). RESULTS: Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with ≥ 2 side effects (p = 0.03). CONCLUSION: Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations.
Asunto(s)
Antibióticos Antituberculosos/sangre , Rifampin/sangre , Tuberculosis Pulmonar/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/farmacocinética , Niño , Preescolar , Monitoreo de Drogas , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rifampin/administración & dosificación , Rifampin/análogos & derivados , Rifampin/farmacocinética , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration-time profiles among OATP1B substrates drugs and endogenous substrates. METHODS: Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined. RESULTS: The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC0-24h of atorvastatin was reasonably correlated with that of pitavastatin (r2 = 0.73) and with the AUC0-4h of fluvastatin (r2 = 0.62) and sufficiently with the AUC0-24h of rosuvastatin (r2 = 0.32). The AUC0-24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r2 = 0.74) and coproporphyrin I (r2 = 0.78), and sufficiently with that of total bilirubin (r2 = 0.30). The AUC0-24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r2 = 0.48-0.70) [corrected]. CONCLUSION: These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.
Asunto(s)
Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/farmacología , Proteína 1 de Transporte de Anión Orgánico/antagonistas & inhibidores , Proteína 1 de Transporte de Anión Orgánico/sangre , Rifampin/sangre , Rifampin/farmacología , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Masculino , Especificidad por Sustrato/efectos de los fármacos , Especificidad por Sustrato/fisiología , Espectrometría de Masas en Tándem/métodosRESUMEN
The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h postdose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.
Asunto(s)
Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/uso terapéutico , Monitoreo de Drogas/métodos , Rifampin/sangre , Rifampin/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Femenino , Humanos , Isoniazida/sangre , Isoniazida/uso terapéutico , Masculino , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/microbiologíaRESUMEN
This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling. Plasma and urine CPI data in the presence/absence of rifampicin were modeled to describe CPI synthesis, elimination clearances, and obtain rifampicin in vivo OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (<25%) in subjects with wildtype SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13 µM) using CPI data was 2-fold lower relative to rosuvastatin. Model-based simulations and power calculations confirmed sensitivity of CPI to identify moderate and weak OATP1B inhibitors in an adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as an endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required.
Asunto(s)
Antibióticos Antituberculosos/farmacocinética , Biomarcadores Farmacológicos/sangre , Simulación por Computador , Coproporfirinas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Modelos Biológicos , Rifampin/farmacocinética , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/efectos adversos , Antibióticos Antituberculosos/sangre , Biomarcadores Farmacológicos/orina , Coproporfirinas/orina , Interacciones Farmacológicas , Genotipo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Dinámicas no Lineales , Variantes Farmacogenómicas , Rifampin/administración & dosificación , Rifampin/efectos adversos , Rifampin/sangre , Medición de Riesgo , Rosuvastatina Cálcica/sangreRESUMEN
Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure-response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.
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Rifampin/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Monitoreo de Drogas/métodos , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Modelos Biológicos , Rifampin/administración & dosificación , Rifampin/sangreRESUMEN
Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a four-drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high-performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.
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Hipertensión Esencial/inducido químicamente , Hipertensión Esencial/diagnóstico , Nicardipino/efectos adversos , Rifampin/uso terapéutico , Anciano , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/uso terapéutico , Antihipertensivos/efectos adversos , Antihipertensivos/sangre , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/sangre , Interacciones Farmacológicas/fisiología , Hipertensión Esencial/sangre , Femenino , Humanos , Nicardipino/sangre , Rifampin/sangreRESUMEN
Matrix effects have been a major concern when developing LC-MS/MS methods for quantitative bioanalysis of cycloserine. Sample handling procedures including solid phase extraction or derivatization have been reported previously by researchers to overcome matrix effects of cycloserine. In the present study, the possibility of reducing matrix effects of cycloserine using protein precipitation coupled with dilution techniques was investigated. Plasma samples were pretreated by protein precipitation with methanol followed by a 40-fold dilution with methanol-water (50:50, v/v). The analyte and the internal standard (mildronate) were chromatographed on a Shim-pack XR-ODS (100 mm × 2.0 mm, 2.2 µm) column using methanol-0.01% formic acid (70:30, v/v) as mobile phase and detected by multiple reaction monitoring mode via positive electrospray ionization. The total run time was only 2 min per sample. The suppression of cycloserine response was reduced with the matrix effects ranging between 80.5 and 87.9%. A lower limit of quantification (LLOQ) of 0.300 µg/mL was achieved using only 10 µL of plasma. The intra- and inter-day precisions were less than 4.8% and the accuracy ranged from -2.6 to 6.6%. The method was successfully applied to a pharmacokinetic study of cycloserine in 30 healthy Chinese male subjects after oral administration of a single dose of cycloserine at 250, 500 and 750 mg under fasting conditions. The newly developed method is simpler, faster, cost-effective, and more robust than previously reported LC-MS/MS methods.
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Artefactos , Cromatografía Líquida de Alta Presión/métodos , Cicloserina/sangre , Cicloserina/farmacocinética , Técnicas de Dilución del Indicador , Espectrometría de Masa por Ionización de Electrospray/métodos , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/química , Antibióticos Antituberculosos/farmacocinética , Análisis Químico de la Sangre/métodos , Cicloserina/química , Humanos , Reproducibilidad de los Resultados , Tamaño de la Muestra , Sensibilidad y EspecificidadRESUMEN
This work introduces a new electrochemical sensor based on polyvinyl pyrrolidone capped CoFe2O4@CdSe core-shell modified electrode for a rapid detection and highly sensitive determination of rifampicin (RIF) by square wave adsorptive stripping voltammetry. The new PVP capped CoFe2O4@CdSe with core-shell nanostructure was synthesized by a facile synthesis method for the first time. PVP can act as a capping and etching agent for protection of the outer surface nanoparticles and formation of a mesoporous shell, respectively. Another important feature of this work is the choice of the ligand (1,10-phenanthroline) for precursor cadmium complex that works as a chelating agent in order to increase optical and electrical properties and stability of prepared nanomaterial. The nanoparticles have been characterized by field emission scanning electron microscopy (FESEM), transmission electron microscope (TEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), UV-vis, photoluminescence (PL) spectroscopy, FT-IR, and cyclic voltammetry techniques. The PL spectroscopy study of CoFe2O4@CdSe has shown significant PL quenching by the formation of CoFe2O4 core inside CdSe, this shows that CoFe2O4 NPs are efficient electron acceptors with the CdSe. It is clearly observed that the biosensor can significantly enhance electrocatalytic activity towards the oxidation of RIF, under the optimal conditions. The novelty of this work arises from the new synthesis method for the core-shell of CoFe2O4@CdSe. Then, the novel electrochemical biosensor was fabricated for ultra-trace level determination of rifampicin with very low detection limit (4.55×10-17M) and a wide linear range from 1.0×10-16 to 1.0×10-7M. The fabricated biosensor showed high sensitivity and selectivity, good reproducibility and stability. Therefore, it was successfully applied for the determination of ultra-trace RIF amounts in biological and pharmaceutical samples with satisfactory recovery data.
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Antibióticos Antituberculosos/sangre , Compuestos de Cadmio/química , Cobalto/química , Técnicas Electroquímicas/instrumentación , Compuestos Férricos/química , Nanopartículas/química , Povidona/química , Rifampin/sangre , Compuestos de Selenio/química , Antibióticos Antituberculosos/análisis , Técnicas Biosensibles/instrumentación , Humanos , Leprostáticos/análisis , Leprostáticos/sangre , Límite de Detección , Nanopartículas/ultraestructura , Reproducibilidad de los Resultados , Rifampin/análisis , ComprimidosRESUMEN
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R2) and accuracy (>93% quality controls, <9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%. Graphical Abstract á .