Population pharmacokinetic of benznidazole, a drug for Chagas disease, in an acute infection murine model

ROCCO, DM; GULIN, JEN; MORONI, S; ALTCHEH, J; GARCÍA BOURNISSEN, F

New Orleans, Louisiana.

Encuentro; 68th Annual Meeting. American Journal of Tropical Medicine and Hygiene; 2018

American Journal of Tropical Medicine and Hygiene

Chagas disease, caused by Trypanosoma cruzi, affects an estimated of 8million people in the world. Benznidazole, one of the only two drugs withproven efficacy, lacks important information on metabolism, specificallypharmacokinetics in both humans and animal models.The objective of thisstudy was to evaluate the pharmacokinetics of benznidazole in a murinemodel of Chagas disease. A total of 28 male, 2 months old, BALB/C mice(16 infected, 12 healthy controls) were administered a single dose of 100mg/kg benznidazole by gavage and blood was sampled by submandibularpuncture at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours. Mice wereinfected (N=16) by intraperitoneal inoculation with 500 parasites, VDstrain, and treated when parasites were detected in blood circulation(15 days post infection). Blood was obtained from every animal (infectedand healthy) at least twice and in some cases three times. Blood sampleswere centrifuged, and serum was precipitated with acetonitrile (1:1) andconserved at -70C until measurement by UHPLC-MS/MS. A populationpharmacokinetics model was implemented with Monolix software (Lixsoft).Population pharmacockinetics followed a one compartment model. The maximum observed concentration was 67.7 μg/ml (Tmax 0.5 h).Absorption was fast (absorption constant ka 3.3h-1), volume of distributionwas 29.9 ml and clearance 16.2ml/h (half life 2hs). No significantdifferences between infected and healthy animals were observed.We observed conserved pharmacokinetics behavior of benznidazolein infected animals compared to healthy mice, providing reassurancethat concentrations obtained in this model reflect those required fordrug effectiveness. Elimination of the drug was fast, suggesting thatonce daily dosing may be insufficient to sustain tissue concentrationsrequired to sterilize the animals (but also confirming the lasting impact ofbenznidazole on the parasite, as beznidazole concentrations are expectedto be low during most of the day with daily dosing).