Assessment of serum pharmacokinetics and urinary excretion of albendazole and its metabolites in human volunteers

Abstract

Background: Soil Transmitted Helminth (STH) infections negatively impact physical and mental development in human populations. Current WHO guidelines recommend morbidity control of these infections through mass drug administration (MDA) using albendazole (ABZ) or mebendazole. Despite major reductions in STH associated morbidity globally, not all programs have demonstrated the expected impact on prevalence of parasite infections. These therapeutic failures may be related to poor programmatic coverage, suboptimal adherence or the exposure of parasites to sub-therapeutic drug concentrations. As part of the DeWorm3 project, we sought to characterize the serum disposition kinetics and pattern of urinary excretion of ABZ and its main metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) in humans, and the assessment of the duration and optimal time point where ABZ and/or its metabolites can be measured in urine as an indirect assessment of an individual's adherence to treatment.

Methodology/principal findings: Consecutive venous blood and urine samples were collected from eight (8) human volunteers up to 72 h post-ABZ oral administration. ABZ/metabolites were quantified by HPLC. The ABZSO metabolite was the main analyte recovered both in serum and urine. ABZSO Cmax in serum was 1.20 ± 0.44 μg/mL, reached at 4.75 h post-treatment. In urine, ABZSO Cmax was 3.24 ± 1.51 μg/mL reached at 6.50 h post-ABZ administration.

Conclusion/significance: Pharmacokinetic data obtained for ABZ metabolites in serum and urine, including the recovery of the ABZ sulphoxide derivative up to 72 h in both matrixes and the recovery of the amino-ABZ sulphone metabolite in urine samples, are suggesting the possibility of developing a urine based method to assess compliance to ABZ treatment. Such an assay may be useful to optimize ABZ use in human patients.

Trial registration: ClinicalTrials.gov NCT03192449.

Fig 1. Serum concentration profiles for ABZ, ABZSO and ABZSO₂.

Comparative (mean ± SD) serum concentration profiles of albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO₂) and albendazole (ABZ) obtained after ABZ administration as a single oral dose (400 mg) to human volunteers. The insert shows the individual area under the concentration vs. time (AUC _0-LOQ) of ABZSO as an indicator of systemic drug availability.

Fig 2. Urine concentration profile for ABZSO.

Albendazole sulphoxide (ABZSO) mean (±SD) urine concentration vs. time profiles obtained after albendazole (ABZ) administration as a single oral dose (400 mg, GlaxoSmithKline) to human volunteers. The insert shows the Individual area under the concentration vs. time (AUC_0-LOQ) of ABZSO after ABZ administration.

Fig 3. ABZSO systemic exposure in serum and urine.

Comparative albendazole sulphoxide (ABZSO) individual serum and urine area under concentration vs time curve (AUC_0-LOQ) obtained from albendazole-treated human volunteers (400 mg, GlaxoSmithKline). The insert shows ABZSO concentrations (mean ± SD) both in serum and urine samples from treated volunteers.

Fig 4. Comparative ABZSO serum and urine concentrations.

Comparative albendazole sulphoxide (ABZSO) serum and urine concentrations (mean ± SD) obtained from human volunteers at 24 and 48 h post albendazole (ABZ)-treatment (400 mg, GlaxoSmithKline). The straight-line represents the limit of quantification (LOQ) value determined for the used methodology. The insert shows correlation between individual ABZSO concentration in serum and urine samples at 48 h post ABZ treatment. The straight-line represents the best-fit line obtained by linear regression analysis.