Abstract
Chagas disease (CD) is recognized as one of the major neglected global tropical diseases. Benznidazole (BNZ) is the drug of choice for the treatment of adults, young infants, and newborns with CD. However, the pharmacokinetics (PK) of BNZ have been poorly evaluated in all age groups, with consequent gaps in knowledge about PK-pharmacodynamic relationships in CD. The purpose of this study was to develop and validate a bioanalytical method to quantify BNZ levels in small-volume whole-blood samples collected as dried blood spots (DBS). The analysis was performed using high-performance liquid chromatography-positive electrospray tandem mass spectrometry. PK evaluation in healthy male volunteers was conducted to verify the correlation between DBS and plasma BNZ concentrations. The calibration curve was linear from 50 to 20,000 ng · ml-1 Intra- and interday precision and bias values were less than 14.87% (n = 9) and 9.81% (n = 27), respectively. The recovery rates ranged from 94 to 100% with no matrix effect. There was no hematocrit level effect in a range of 20 to 70%. The PK results obtained from DBS and plasma were comparable (r2 = 0.8295) and equivalent to previously published information on BNZ. BNZ in DBS was stable at room temperature for more than one year. This article describes the first microsampling method for measuring BNZ levels in DBS that has the potential to facilitate broad implementation of PK in clinical trials involving adult and pediatric patients in remote areas and helps to address existing knowledge gaps in the treatment of CD.
Highlights
Chagas disease (CD) is recognized by the World Health Organization (WHO) as one of the major neglected global tropical diseases
There are a few methods reported in the literature for BNZ quantification in different matrices, notably differential pulse polarography high-performance liquid chromatography (HPLC) with ultraviolet detection [4, 11, 12], ultrahigh-performance liquid chromatography (UHPLC) with ultraviolet detection [13], and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [5, 14]
The method used demonstrated excellent chromatographic selectivity, with no endogenous or metabolite interference at the retention times for both BNZ and the internal standard (IS) in six different sources of whole blood and in the presence of local anesthetic drugs
Summary
Chagas disease (CD) is recognized by the World Health Organization (WHO) as one of the major neglected global tropical diseases. 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]. After a long period with limited information about pharmacokinetic (PK) parameters for BNZ [8, 9], various studies in patients and healthy volunteers have been published. Pediatric population PK was assessed in one clinical study, which showed lower BZN concentrations than those reported in adults, as well as fewer adverse events [10]. There are a few methods reported in the literature for BNZ quantification in different matrices (tissues, plasma, serum, urine, and milk), notably differential pulse polarography high-performance liquid chromatography (HPLC) with ultraviolet detection [4, 11, 12], ultrahigh-performance liquid chromatography (UHPLC) with ultraviolet detection [13], and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [5, 14]
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