High-Fat Breakfast Increases Bioavailability of Albendazole Compared to Low-Fat Breakfast: Single-Dose Study in Healthy Subjects

Purpose: Albendazole is a benzimidazole carbamate drug with anthelmintic and antiprotozoal activity against intestinal and tissue parasites. It has been described that the administration with meals increases albendazole absorption. Our aim was to compare the systemic exposure in healthy volunteers of two albendazole formulations after a single oral dose under fed conditions and to evaluate the effect of breakfast composition on albendazole and albendazole sulfoxide bioavailability.Methods: 12 healthy volunteers were included in a 4-period, 4-sequence, crossover, open, randomized, bioequivalence clinical trial, including two stages to compare two formulations of albendazole. Single oral doses of 400 mg albendazole were administered under fed conditions (a low-fat breakfast in first stage and a high-fat breakfast in the second) separated by 7-day washout periods. Plasma albendazole and albendazole sulfoxide concentrations were measured by HPLC-MS/MS.Findings: Albendazole absorption was clearly influenced by the meal composition. A high-fat breakfast increased albendazole and albendazole sulfoxide area under the concentration–time curve (AUC) and maximum concentration (Cmax) by double, compared to a low-fat breakfast. The bioavailability of the two formulations was very similar, although the sample size was not sufficient to demonstrate bioequivalence because the intraindividual variability of albendazole was approximately 60%.Implications: The higher albendazole and albendazole sulfoxide levels when administered with a high-fat meal could be of importance in clinical practice. Since albendazole labeling recommends its administration with meals, it is necessary to insist on taking it with a fatty meal so that the effectiveness of albendazole is not compromised.

DEVELOPMENT OF METHODS FOR QUANTITATIVE DETERMINATION OF ALBENDAZOLE AND ITS METABOLITES IN BIOLOGICAL TISSUES USING HPLC / FLD

This manuscript presents the results of developed method is intended for clinical and pharmaceutical studies of veterinary drugs based on the active substances albendazole ([5-(propylthio)-1H-benzimidazol-2yl]carbamic acid methyl ester) and its main metabolites, albendazole sulfoxide, albendazole sulfone, and albendazole-2- aminosulfone in sheep muscles. Tissue samples were made alkaline with sodium carbonate, extracted twice with acetonitrile and degreased with hexane. The extracts are further purified using a series of liquid-liquid extraction and solid phase extraction. After concentration and drying, the dry residue was recovered in the mobile phase. Separation was performed on an inverted phase Acclaim 120 C18 column using acetonitrile and phosphate buffer as the mobile phase. The gradient mode of eluents was used during 12 min at a flow rate of 1,8 ml/min. The peak retention time of albendazole 2-aminosulfoam is 3,0 min, albendazole sulfoxide is 3,9 min, albendazole sulfone is 4,8 min, and the retention time of albendazole peak is 6,6 min. The specificity of the analytical method was checked by comparing the chromatographic separation of a sample of muscle tissue enriched with a standard solution of a mixture of albendazole and its metabolites at the level of MDR (100 μg/kg) and a sample of muscle tissue placebo. The validation parameters of the method “recovery” and “coefficient of variation” were considered in accordance with the criteria of Council Directive 2002/657/EC. The procedure of sample preparation of fortified tissues to construct calibration graphs is described in the manuscript. The mean recovery from fortified muscle tissue in the range of 50-150 μg/kg albendazole, albendazole sulfoxide, albendazole sulfone and albendazole 2-aminosulfon was 100.2; 100.9; 100.7 and 100.2%, respectively. The average coefficient of variation for each compound was ≤ 10%. The method is linear in the concentration range of 25.0 - 200.0 μg/kg of each analyte. The results obtained in the study of the linearity of this technique were used to estimate the correctness and convergence. The accuracy of the measurements was evaluated by examining the known amounts of analytes added to the control muscle tissue. Recovery data are acceptable because they are within ± 10% of the target value. The method has sufficient convergence (accuracy). The evaluation of the intermediate accuracy of albendazole and its metabolites was assessed on three different days of analysis. The limit of detection for albendasole is 0.4 μg/kg. The average CV for each compound was <10%. The procedure was confirmed and then applied to determination albendazole and its metabolites in the sheep muscle tissue obtained after feeding animals with the veterinary drug albendazole. The HPLC/FLD method can be used for withdrawal time albendazole and its metabolites.

Assessment of the Performance of Solid Phase Extraction Based on Pipette Tip Employing a Hybrid Molecularly Imprinted Polymer as an Adsorbent for Enantioselective Determination of Albendazole Sulfoxide

Herein, an organic–inorganic hybrid molecularly imprinted polymer (MIP) was successfully synthesized with albendazole sulfoxide (ABZSO) as a template and 3-(trimethoxysilyl)propyl methacrylate, a bifunctional group compound, as a single cross-linking agent. In this study, a simple method using HPLC–DAD was developed for the determination of ABZSO enantiomers in human urine using pipette tip-based molecularly imprinted polymer solid phase extraction (PT–MIP–SPE). Enantioseparation with satisfactory retention times (5.17 and 7.09 min), acceptable theoretical plates (N = 4,535 and 5,091) and strong resolution (Rs = 5.45) was performed with an Agilent® Eclipse Plus C18 (100 mm × 4.6 mm, 3.5 μm) coupled with a Chiralpak® IA column (100 mm × 4.6 mm, 3 μm), a mixture with ethanol:water (50:50, v/v) as the mobile phase, temperature at 40°C, flow rate at 0.9 mL min−1 and λ = 230 nm. Thereafter, certain parameters affecting the PT–MIP–SPE were investigated in detail and the better conditions were: 300 μL of water as washing solvent, 500 μL of ethanol:acetic acid (9:1, v/v) as eluting solvent, 20 mg of MIP, 500 μL of human urine at pH 9 and no addition of NaCl. Recoveries/relative standard deviation (RSD%) for (R)-(+)-ABZSO and (S)-(−)-ABZSO were 78.2 ± 0.2% and 69.7 ± 1.7%, respectively.

Pharmacokinetics of Albendazole, Albendazole Sulfoxide, and Albendazole Sulfone Determined from Plasma, Blood, Dried-Blood Spots, and Mitra Samples of Hookworm-Infected Adolescents

ABSTRACT Albendazole is an effective anthelmintic intensively used for decades. However, profound pharmacokinetic (PK) characterization is missing in children, the population mostly affected by helminth infections. Blood microsampling would facilitate PK studies in pediatric populations but has not been applied to quantify albendazole’s disposition. Quantification methods were developed and validated using liquid chromatography-tandem mass spectrometry to analyze albendazole and its metabolites albendazole sulfoxide and albendazole sulfone in wet samples (plasma and blood) and blood microsamples (dried-blood spots [DBS]; Mitra). The use of DBS was limited by a matrix effect and poor recovery, but the extraction efficiency was constant throughout the concentration range. Hookworm-infected adolescents were venous and capillary blood sampled posttreatment with 400 mg albendazole and 25 mg/kg oxantel pamoate. Similar half-life (t1/2 = ∼1.5 h), time to reach the maximum concentration (tmax = ∼2 h), and maximum concentration (Cmax = 12.5 to 26.5 ng/ml) of albendazole were observed in the four matrices. The metabolites reached Cmax after ∼4 h with a t1/2 of ca. 7 to 8 h. A statistically significant difference in albendazole sulfone’s t1/2 as determined by using DBS and wet samples was detected. Cmax of albendazole sulfoxide (288 to 380 ng/ml) did not differ among the matrices, but higher Cmax of albendazole sulfone were obtained in the two microsampling devices (22 ng/ml) versus the wet matrices (14 ng/ml). In conclusion, time-concentration profiles and PK results of the four matrices were similar, and the direct comparison of the two microsampling devices indicates that Mitra extraction was more robust during validation and can be recommended for future albendazole PK studies.

Albendazole Sulfoxide Plasma Levels and Efficacy of Antiparasitic Treatment in Patients With Parenchymal Neurocysticercosis

BackgroundThe efficacy of albendazole therapy in patients with parenchymal neurocysticercosis (NCC) is suboptimal. Plasma levels of albendazole sulfoxide (ASOX), the active metabolite of albendazole, are highly variable among patients. We hypothesized that high ASOX plasma levels during albendazole therapy may be associated with an increased antiparasitic efficacy.MethodsASOX plasma levels were measured at treatment day 7 in 118 patients with parenchymal NCC enrolled in a treatment trial. The relationships between increasing ASOX plasma levels with the proportion of cysts resolved and the proportion of patients with complete cyst resolution (evaluated by 6-month brain magnetic resonance) were assessed.ResultsThere was a trend toward a higher proportion of cysts resolved and a higher proportion of patients cured with increasing quartiles of ASOX plasma levels. In patients with 3 or more brain cysts, the regression analysis adjusted by the concomitant administration of praziquantel (PZQ) showed a 2-fold increase in the proportion of cysts resolved (risk ratio [RR], 1.98; 95% confidence interval [CI], 1.01–3.89; P = .048) and 2.5-fold increase in the proportion of patients cured (RR, 2.45; 95% CI, .94–6.36; P = .067) when ASOX levels in the highest vs the lowest quartile were compared. No association was found in patients with 1–2 brain cysts.ConclusionsWe suggest an association between high ASOX plasma levels and increased antiparasitic efficacy in patients with parenchymal NCC. Nonetheless, this association is also influenced by other factors including parasite burden and concomitant administration of PZQ. These findings may serve to individualize and/or adjust therapy schemes to avoid treatment failure.