INBIOMED   24026
INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Refining strategies for pharmacokinetic studies: application in a mouse model of Trypanosoma cruzi acute infection
Autor/es:
GULIN, ERNESTO; ALTCHEH, JAIME; ROCCO, DANIELA MARISA; GARCÍA-BOURNISSEN, FACUNDO
Lugar:
Mar del Plata
Reunión:
Otro; Reunión Anual de Sociedades Biocientíficas.; 2019
Institución organizadora:
SAIC-SAFE-SAB-SAP-AACYTAL-NANOMEDar-HCS
Resumen:
Benznidazole (BZ) is one of the two available nitroheterocyclic drugs for Chagas disease treatment. The lack of pharmacokinetic (PK) information in human andanimal models hampers the development of suitable treatment strategies. Classical PK studies require high volumes of blood and a group of mice for each PK time point. The objective of this work was to develop a BZ PK model in infected mice with T. cruzi, applying population PK strategies to reduce the number of animals and refine the procedures. Twenty-eight 2-months old male BALB/cJ mice were treated with a single 100 mg/kg dose of BZ by gavage; blood was sampled at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 h. Mice (n= 12) were infected by i.p. route with 500 trypomastigotes of T. cruzi VD strain and treated with BZ at parasitemia onset. The protocol was approved by the local IACUC (#2017-10). Blood was obtained by sub-mandibular puncture, which allowed obtaining enough volume for BZ analysis but also permitted to take multiple samples from each mouse. Blood samples were centrifuged, serum was precipitated with acetonitrile (1:1) and conserved at -70oC until BZ measurement by UHPLC-MS/MS. A population PK model was developed using Monolix software (Lixsoft). BZ population PK followed a one compartment model with first order oral absortion; the maximumobserved concentration (Cmax) was 67.7 μg/ml at 0.5 h from drug administration. Absorption was fast (ka 4.3h-1), the distribution volume was 30.3 ml and clearance 15.8 ml/h (estimated half-life: 1.3 h). Significant differences between infected and control mice were only observed in the distributionvolume (non-linear mixed effects regression model, p