Résumé
BackgroundAlbendazole is an orally administered anti-parasitic medication with widespread usage in a variety of both programmatic and clinical contexts. Previous work has shown that the drug's pharmacologically active metabolite, albendazole sulfoxide, is characterised by substantial inter-individual pharmacokinetic variation. This variation might have implications for the efficacy of albendazole treatment, but current understanding of the factors associated with this variation remains incomplete. Methodology/Principal findingsWe carried out a systematic review to identify references containing temporally disaggregated data on the plasma concentration of albendazole and/or (its pharmacologically-active metabolite) albendazole sulfoxide following a single oral dose. These data were then integrated into a mathematical modelling framework to infer albendazole sulfoxide pharmacokinetic parameters and relate them to characteristics of the groups being treated. These characteristics included age, weight, sex, dosage, infection status, and whether patients had received a fatty meal prior to treatment or other drugs alongside albendazole. Our results highlight a number of factors systematically associated with albendazole sulfoxide pharmacokinetic variation including age, existing parasitic infection and receipt of a fatty meal. Age was significantly associated with variation in albendazole sulfoxide systemic availability and peak plasma concentration achieved; as well as the clearance rate (related to the half-life) after adjusting for variation in dosage due to differences in body weight between children and adults. Receipt of a fatty meal prior to treatment was associated with increased albendazole sulfoxide systemic availability (and by extension, peak plasma concentration and total albendazole sulfoxide exposure following the dose). Parasitic infection (particularly echinococcosis) was associated with altered pharmacokinetic parameters, with infected populations displaying distinct characteristics to uninfected ones. Conclusions/SignificanceThese results highlight the extensive inter-individual variation that characterises albendazole sulfoxide pharmacokinetics and provide insight into some of the factors associated with this variation.
Author summaryAlbendazole is a broad-spectrum anti-parasitic medication widely used in the treatment of a variety of parasitic worm infections. Previous studies have demonstrated marked variation in the pharmacokinetics of albendazole (and its pharmacologically active metabolite albendazole sulfoxide), leading to substantial inter-individual variability in blood plasma concentrations of albendazole sulfoxide following an oral dose of albendazole. This variation is thought to have consequences for treatment success but our understanding of the factors driving this variation remains incomplete. In this study, we carried out a systematic review to identify references with data on albendazole and albendazole sulfoxide concentrations in plasma following a single oral dose. We then fitted a mathematical model of albendazole sulfoxide pharmacokinetics to these data to infer key pharmacokinetic parameters and relate them to characteristics of the groups being treated. We found that: 1) receipt of a fatty meal prior to treatment was associated with increased albendazole sulfoxide systemic availability; 2) the half-life of albendazole sulfoxide varied significantly with age, and 3) both echinococcosis and neurocysticercosis were associated with altered albendazole sulfoxide pharmacokinetic profiles compared to healthy individuals. Our work provides insight into some of the factors systematically associated with variation in albendazole sulfoxide pharmacokinetics.