Population pharmacokinetics modeling of albendazole and its active metabolite, albendazole sulfoxide in mass drug administration against lymphatic filariasis

Samenvatting

ABSTRACT Albendazole (ALB), a benzimidazole antiparasitic, is widely used in mass drug administration (MDA) campaigns against lymphatic filariasis (LF). It is rapidly metabolized to its active form, albendazole sulfoxide (ALB-OX), which exhibits considerable interindividual variability (IIV) in pharmacokinetics (PK). This variation may affect ALB efficacy in MDA programs. We developed a population pharmacokinetic (PopPK) model characterizing ALB and ALB-OX exposure and identifying demographic and clinical covariates contributing to IIV in patients with LF and healthy individuals. Plasma concentration-time data were pooled from three clinical studies involving ALB co-administered with ivermectin and diethylcarbamazine. Nonlinear mixed-effects modeling was conducted using Phoenix NLME. Covariate effects (e.g., sex, age, infection status) were assessed, and model validation employed visual predictive checks and bootstrapping. Simulations explored covariate impact on exposure. A joint two-compartment model with transit absorption for ALB and pre-systemic ALB-OX formation best described the data. Sex significantly influenced ALB-OX clearance and volume of distribution, with males exhibiting higher clearance and lower exposure. Body weight, age, and LF infection status did not significantly affect PK parameters. Simulations confirmed 33% lower ALB-OX levels in males compared to females following a 400 mg oral ALB dose. This is the first PopPK model of ALB and ALB-OX in LF-endemic populations. It highlights sex as a key covariate explaining IIV in ALB-OX exposure, with implications for optimized dosing in MDA programs. Further studies incorporating pharmacogenetics and pediatric data are warranted. This study is registered with ClinicalTrials.gov as NCT04410406 , NCT02845713 , and NCT03664063 .