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1.
Ther Drug Monit ; 38(5): 573-8, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27631464

RESUMEN

BACKGROUND: Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. METHODS: Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. RESULTS: Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%. CONCLUSIONS: Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.


Asunto(s)
Interacciones Farmacológicas , Linezolid/administración & dosificación , Linezolid/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/agonistas , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Antibacterianos/sangre , Antibacterianos/farmacocinética , Inductores de las Enzimas del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Humanos , Unidades de Cuidados Intensivos , Linezolid/sangre , Modelos Biológicos
2.
Br J Clin Pharmacol ; 80(3): 525-33, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25808018

RESUMEN

AIMS: The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics. METHODS: Twenty patients (m/f 15/5, age 25-86 years, body weight 60-121 kg, APACHE II 7-40, estimated glomerular filtration rate 19-157 ml min(-1) , albumin 11.7-30.1 g l(-1) , total bilirubin <0.1-36.1 mg dl(-1) ) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis-Menten kinetics. RESULTS: For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6-24.5 l), the half-life 14.5 h (10.0-25.5 h) and the clearance 0.96 l h(-1) (0.55-1.28 l h(-1) ). The clearance of unbound drug was 1.91 l h(-1) (1.46-6.20 l h(-1) ) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h(-1) , r(2) = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2-44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (≤1 mg l(-1) ) throughout the whole dosing interval. CONCLUSIONS: Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient.


Asunto(s)
Antibacterianos/sangre , Ceftriaxona/sangre , Albúmina Sérica/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Simulación por Computador , Enfermedad Crítica/terapia , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular , Humanos , Unidades de Cuidados Intensivos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Unión Proteica , Factores de Tiempo
3.
J Pharm Sci ; 107(2): 739-744, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28927988

RESUMEN

Tigecycline, a tetracycline derivative, shows atypical plasma protein binding behavior. The unbound fraction decreases with increasing concentration at therapeutic concentrations. Moreover, uncertainty exists about the magnitude of tigecyline's protein binding in man. Unbound fractions between 2.5% and 35% have been reported in plasma from healthy volunteers, and between 25% and 100% in patients, respectively. In the present study, the protein binding of tigecycline has been investigated by ultrafiltration using different experimental conditions. Whereas temperature had only a marginal influence, the unbound fraction at 0.3/3.0 mg/L was low at pH 8.2 (9.4%/1.9%) or in unbuffered pooled plasma (6.3%/1.2%), compared with plasma buffered with HEPES to pH 7.4 (65.9%/39.7%). In experiments with phosphate buffer and EDTA, the concentration dependency was markedly attenuated or abolished, which is compatible with a cooperative binding mechanism involving divalent cations such as calcium. The unbound fraction in clinical plasma samples from patients treated with tigecycline was determined to 66.3 ± 13.7% at concentrations <0.3 mg/L compared with 41.3 ± 16.0% at >1 to <5 mg/L. To summarize, tigecycline appears to be only moderately bound to plasma proteins as determined by ultrafiltration, when a physiological pH is maintained.


Asunto(s)
Minociclina/análogos & derivados , Plasma/metabolismo , Unión Proteica/fisiología , Proteínas Sanguíneas/metabolismo , Humanos , Minociclina/metabolismo , Tigeciclina , Ultrafiltración/métodos
4.
Artículo en Inglés | MEDLINE | ID: mdl-24878831

RESUMEN

Ultrafiltration is a rapid and convenient method to determine the free concentrations of drugs. In the present work, we aimed to develop an ultrafiltration method which is appropriate for routine determination of the free fraction of vancomycin and highly protein bound beta-lactams such as ertapenem, ceftriaxone and cefazolin in plasma from intensive care unit patients. Different filter types and experimental conditions (molecular weight cut-off, centrifugal force and time, pH, temperature) were evaluated and found to have influence on the result. In the final protocol, serum or plasma was buffered to pH 7.4-7.5, ultrafiltered at 1000×g at 37°C for 20min using Nanosep Omega 10K filters and subsequently analysed for the antibiotics by RP-HPLC with UV detection. The data from our investigation suggest to aim physiological conditions, i.e. 37°C and pH 7.4, and low to moderate relative centrifugal forces in order to get reliable results. With regard to the chromatographic separation, modulation of the pH in the range of 2.5-7.0 allows to determine several beta-lactams isocratically and/or to avoid interferences by co-administered drugs.


Asunto(s)
Cefazolina/sangre , Ceftriaxona/sangre , Vancomicina/sangre , beta-Lactamas/sangre , Estabilidad de Medicamentos , Ertapenem , Humanos , Unión Proteica , Ultrafiltración/métodos
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