CHARACTERIZATION OF POPULATION PHARMACOKINETICS AND ASSOCIATED INTERINDIVIDUAL VARIABILITY OF DRUGS USED IN MASS DRUG ADMINISTRATION AGAINST LYMPHATIC FILARIASIS

Abstract

Lymphatic filariasis (LF) is a mosquito-borne filarial infection that affects the lymphatic system. The progression of the disease is associated with severe comorbidities and social stigma among patients. The World Health Organization has categorized the disease as a public health problem, and it has been targeted by mass drug administration (MDA) campaigns over the past two decades. Several preventive chemotherapies have been used in MDA campaigns against LF, including a combination of three anti-filarial drugs (IDA therapy): albendazole (ALB), diethylcarbamazine (DEC), and ivermectin (IVM). Other antiparasitic drugs, such as moxidectin (MOX), are still under investigation for their activity against LF. High inter-individual variability (IIV) in pharmacokinetics has been reported with anti-filarial drugs used in MDA. Addressing IIV, especially for drugs that exhibit significant variability, is critical for optimal dosing to ensure maximum drug efficacy and limiting toxicities. This dissertation aims to characterize the population pharmacokinetics (PopPK) of anti-filarial drugs used in MDA against LF, investigate the reported high IIV, and evaluate different dosing regimens to simplify the existing weight-based dosing. Utilizing drug exposure data from populations living in areas where LF is prevalent, PopPK models for IDA therapy and MOX were developed using non-linear mixed-effect modeling. The presented models showed a good ability to describe the PopPK of MDA drugs, which was evident by the goodness of fit criteria. The covariates analysis showed that sex was a significant explaining part of IIV observed with IVM and DEC. Moreover, the clearance of albendazole sulfoxide (ALB-OX), the active metabolite of ALB, was different between men and women. Weight and microfilaria count at baseline significantly explained part of the variability associated with the volume of distribution of DEC and MOX, respectively. Models-based simulation findings demonstrated that those factors have also affected drug exposure parameters, including maximum plasma concentration (Cmax) and area under the curve (AUC) of IDA and MOX. In MDA campaigns, IVM and DEC are dose-based on body weight, and this dosing regimen could be challenging due to logistic concerns. We have performed a model-based simulation to simulate IVM and DEC exposure after various non-weight-based dosing regimens to simplify the dosing in MDA campaigns. For IVM, the model-based simulation showed higher drug exposure with the experimental 18 mg fixed dose regimen compared with weight-based dosing; however, the increase in drug exposure was relatively small and remained below the plasma threshold associated with emergent side effects. Height-based DEC dosing decreased variability in drug exposure observed with weight-based dosing. In conclusion, the presented work uniquely described PopPK and IIV linked with IDA and MOX therapy in MDA-eligible populations. The developed models can be used for future dose-informing studies to optimize drug dosing and help achieve LF eradication goals.