Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

Abstract

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.

Experimental and Clinical Treatment of Chagas Disease: A Review

“…In addition, a phase I, open-label, nonrandomized pharmacokinetic study of BZ using eight healthy adult volunteers, performed by the BERENICE project, show similar results. 183 These findings support the rationale of proposing a lower BZ dose.…”

Clinical and pharmacological profile of benznidazole for treatment of Chagas disease

“…A recent Phase I, open-label, nonrandomized pharmacokinetic study with eight healthy adult volunteers investigated the PK of a single 100 mg dose of BZN and used the calculated non-compartmental PK parameters to simulate two multiple-dose administration regimens: 100 mg administered every 8 h and 150 mg administered every 12 h. Observed PK parameters were similar to those in other studies, but the authors concluded that both simulated regimens reached steady-state concentrations above the minimum experimental therapeutic dose. Men had lower median Cmax and higher median volume of distribution than women, but the limited number of individuals (N = 4 per group) precludes definitive conclusions on the influence of sex on BZN PK [73]. The BZN label mentions that food does not seem to affect absorption of the medication, according to comparative bioavailability studies performed for registration of the product in the USA [36].…”

“…BENDITA (BEnznidazole New Doses Improved Treatment and Associations) is a Phase II randomized, multi-center study in Bolivia assessing benznidazole at shorter or intermittent dosing regimens and in combination with E1224, compared to placebo, in patients with chronic CD (ClinicalTrials.gov Identifier: NCT03378661). MULTIBENZ (Evaluation of Different Benznidazole Regimens for the Treatment of Chronic Chagas Disease) (BERENICE Project, ClinicalTrials.gov Identifier: NCT03191162) is testing a modified regimen of BZN for treatment of CD in the chronic phase compared to the standard scheme [73].…”

“…Ongoing investigations aim to optimize BZN therapy by adjusting the current standard regimen [73,80,83] or by combining BZN with new chemical entities [80][81][82]. These studies are assessing alternatives to improve safety while improving or at least maintaining the efficacy of BZN.…”

Dried Blood Spot Technique-Based Liquid Chromatography-Tandem Mass Spectrometry Method as a Simple Alternative for Benznidazole Pharmacokinetic Assessment

“…BNZ is widely accepted as the drug of choice for acute and early chronic-phase Chagas disease due to the large body of evidence from adequate and well-controlled studies ( 4 ). Safety and tolerability issues (such as hypersensitivity reactions, allergic dermopathy, and painful peripheral neuropathy) ( 5 – 7 ), as well as the long treatment duration, have limited broader use of the current compounds, particularly in the adult population, but these treatments have been shown to be manageable when used at a recommended dose of 5 mg/kg of body weight/day ( 8 ).…”