Farmacocinética y farmacodinamia de ceftarolinaPharmacokinetics and pharmacodynamics of ceftaroline

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Resumen

Ceftarolina se administra por vía intravenosa en forma de profármaco, ceftarolina fosamil, que es hidrolizado rápidamente por las fosfatasas plasmáticas a ceftarolina activa. En general, la farmacocinética de ceftarolina no difiere ostensiblemente de la de otras cefalosporinas. Se ha observado un aumento proporcional tanto de la concentración plasmática máxima (Cmax) como del área bajo la curva (ABC) cuando se administra en dosis crecientes, lo que demuestra su famacocinética lineal. La mitad de la dosis de ceftarolina se excreta por vía renal en forma activa. Los parámetros farmacocinéticos de ceftarolina administrada por vía intramuscular a diversas especies de animales fueron comparables a los observados por vía intravenosa, por lo que sería oportuna la investigación clínica de este fármaco por esta vía alternativa. Los pacientes con alteración de la función renal moderada-grave y los sometidos a hemodiálisis requieren ajuste de dosis. Se dispone de limitada experiencia sobre la farmacocinética de ceftarolina en niños, que ha dado lugar a diversas pautas estratificadas por grupos de edad. La farmacodinamia de esta cefalosporina se ha estudiado en modelos de infección animal o in vitro causados principalmente por Staphylococcus aureus (incluyendo SARM, cepas con sensibilidad intermedia a vancomicina [hVISA o hGISA]) y por cepas de Streptococcus pneumoniae con distinta sensibilidad a penicilina.

Al tratarse de un antibiótico dependiente del tiempo, el indicador farmacocinético/farmacodinámico (PK/PD) más estudiado ha sido el tiempo del intervalo durante el cual las concentraciones del antibiótico se mantienen por encima de la concentración mínima inhibitoria (CMI), calculado tanto como fármaco total (T > CMI) como en base a la fracción de fármaco libre (fT > CMI). Las simulaciones PK/PD efectuadas en estos modelos, desarrollados a partir de concentraciones obtenidas con las dosis habituales en humanos, han demostrado que ceftarolina presenta un buen comportamiento PK/PD frente a estos microorganismos, incluyendo las cepas con sensibilidad disminuida a vancomicina, linezolid o daptomicina.

Abstract

Ceftaroline is administered intravenously in the form of a prodrug, ceftaroline fosamil, which is rapidly hydrolyzed by plasma phosphatases to its active form, ceftaroline. In general, the pharmacokinetics of ceftaroline differ little from those of other cephalosporins. A proportional increase in both the peak plasma concentration (Cmax) and the area under the curve (AUC) have been observed when the drug is administered in increasing doses, which demonstrates its linear pharmacokinetics. Half the dose of ceftaroline is excreted actively through the kidneys. The pharmacokinetic parameters of ceftaroline administered through the intramuscular route in diverse animal species were similar to those observed when the drug was administered intravenously and consequently clinical research into ceftaroline administered through this alternative route would be appropriate. Patients with moderate-severe alterations of renal function and those undergoing hemodialysis require dose adjustments. There is limited experience of the pharmacokinetics of ceftaroline in children, which has given rise to several schedules stratified by age groups. The pharmacodynamics of the drug have been studied in models of animal infection and in in vitro infections caused mainly by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA], strains with intermediate vancomycin sensitivity [hVISA or hGISA]) and by Streptococcus pneumoniae strains with distinct sensitivities to penicillin.

Because ceftaroline is a time-dependent antibiotic, the most widely studied pharmacokinetic/pharmacodynamic (PK/PD) indicator is the time interval during which drug concentrations are maintained above the minimum inhibitory concentration (MIC), calculated both as total drug (T > MIC) and as free fraction of the drug (fT > MIC). The PK/PD simulations carried out in these models, developed on the basis of the concentrations obtained with routine doses in humans, have shown that ceftaroline has a good PK/PD profile against these microorganisms, including strains with reduced sensitivity to vancomycin, linezolid, and daptomycin.

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