Despite its toxicity and low efficacy in the chronic phase, benznidazole is the drug of choice in Chagas disease. Scarce information about pharmacokinetics and pharmacodynamics of benznidazole has been published. We performed a phase I, open-label, nonrandomized pharmacokinetic study of benznidazole (Abarax) conducted with 8 healthy adult volunteers at the Infectious Diseases Department of the Vall d'Hebron University Hospital (Barcelona, Spain). The separation and detection of benznidazole were performed on a Waters Acquity ultraperformance liquid chromatography system (UPLC) coupled with a Waters Xevo TQ MS triple quadrupole mass spectrometer. The pharmacokinetic parameters were calculated based on a noncompartmental body model using Phoenix WinNonlin version 6.3 software. Furthermore, computational simulations were calculated for the multiple-dose administration at two dose regimens: 100 mg of benznidazole administered every 8 h and 150 mg of benznidazole administered every 12 h. After benznidazole administration, the median area under the concentration-time curve from time zero to time t (AUC 0 -t ) and extrapolated to infinity (AUC 0 -∞ ) were about 46.4 g · h/ml and 48.4 g · h/ml, respectively. Plasma benznidazole concentrations peaked at 3.5 h, with maximal concentrations of 2.2 g/ml, and benznidazole exhibited a terminal half-life of 12.1 h. The median maximum concentration (C max ) of benznidazole was lower in men than in women (1.6 versus 2.9 g/ml), and median volume of distribution (V) as a function of bioavailability (F) was higher in men than in women (125.9 versus 88.6 liters). In conclusion, dose regimens (150 mg/12 h or 100 mg/8 h) reached a steady-state range concentration above of the minimum experimental therapeutic dose. Sex differences in the benznidazole pharmacokinetics were observed; mainly, men had lower C max and higher V/F than women.
• Apixaban is a novel oral anticoagulant that has not been studied in pregnant patients.• Our objective was to determine the rate and extent of the placental transfer of apixaban.• Apixaban rapidly crosses the ex vivo term human placenta from maternal to fetal circulation.• Fetal apixaban levels in vivo are estimated to be 35-90% of the corresponding maternal levels.Summary. Background: Apixaban is a novel oral anticoagulant that is increasingly being prescribed to women of reproductive age. However, information regarding its placental transfer is non-existent. Objective: To determine the rate and extent of placental transfer of apixaban, using the human placenta ex vivo. Methods: Placentae collected after Caesarean or vaginal delivery of healthy term infants were perfused in the respective maternal and fetal circulation. At the start of the experiment, apixaban was added to the maternal circulation at a concentration of 150 ng mL À1 , and samples from maternal and fetal reservoirs were collected over 3 h. Results: There was a rapid decline of apixaban in the maternal compartment, followed by emergence in the fetal compartment with a median fetal-to-maternal drug concentration ratio of 0.77 (interquartile range [IQR], 0.76-0.81) and fetal concentration of 39.0 ng mL À1 (IQR, 36.8-40.6) after 3 h (n = 5).The perfusion results were subsequently adjusted to account for differences in the concentration of plasma proteins in maternal and fetal blood, as apixaban remains highly bound to albumin and alpha-1 acid glycoprotein. After the adjustment, the predicted fetal-to-maternal ratio of total (bound plus unbound) apixaban concentrations in vivo ranged from 0.35 to 0.90. Conclusions: We conclude that unbound apixaban rapidly crosses from the maternal to fetal circulation. We further predict that total apixaban concentrations in cord blood in vivo are 35-90% of the corresponding maternal levels, suggesting that apixaban could have a possible adverse effect on fetal and neonatal coagulation.
Objectives To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug’s biodistribution in mice. Methods Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. Results Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas’ disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). Conclusions Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas’ disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
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