RESUMEN
A sensitive and rapid ultra-performance liquid chromatography coupled with -tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine ceftibuten (CTB) and sulbactam (SUL) in human plasma. An ACQUITY UPLC HSS T3 C18 (2.1 × 100 mm), 1.8 µm column with gradient elution of water (0.1% formic acid) and acetonitrile was used for separation at a flow rate of 0.2 mL/min. This method involves a simple sample preparation with acetonitrile. The calibration curves of CTB and SUL in plasma showed good linearity over the concentration range of 0.50-25 µg/mL and with a correlation coefficient (r2) >0.99. This method was validated in terms of selectivity, linearity, precision, accuracy and stability. High precision was obtained with coefficients of variation <15%. Excellent recovery in the range of 90-104% was achieved for CTB and SUL was 86-110%. The method has the potential utility to support pharmacometric modeling in clinical practice and biopharmaceutic studies.
RESUMEN
PURPOSE: To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. METHODS: A prospective study was developed in 50 children (1-15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. RESULTS: A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. CONCLUSIONS: The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.