Pharmacokinetic-Pharmacodynamic Modelling of anti-Wolbachia Agents

Waterhouse, David (2019) Pharmacokinetic-Pharmacodynamic Modelling of anti-Wolbachia Agents. PhD thesis, University of Liverpool.

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Abstract

Lymphatic filariasis (LF) and onchocerciasis are priority neglect tropical disease that together infect more than 84 million people worldwide, with an at-risk population of 1.5 billion people, meaning the need for mass drug administration programmes over sustained period of time is a must. Current and historical chemotherapeutic approaches to LF and onchocerciasis control have relied heavily upon drugs with only microfilaricidal activity. Failure to develop a macrofilaricide capable of being deployed within the mass drug administration (MDA) environment has led to an over reliance on the current frontline drugs of ivermectin, albendazole and diethylcarbamazine. The formation of the anti-Wolbachia (AWOL) consortium was conceived to meet the urgent global need for a safe and reliable macrofilaricidal drug that can accelerate the elimination programmes currently being deployed for the treatment of LF and onchocerciasis. The AWOL consortium demonstrated that by targeting the obligated endosymbiont bacteria Wolbachia with doxycycline (DOX) treatment, a safe macrofilaricidal activity could be delivered that demonstrated superior therapeutic outcomes in comparison to current standard anti-filarial drugs (SAFD). The establishment of DOX as a novel treatment regimen for filarial nematode infections is constrained as DOX is contraindicated in children under eight years old and in pregnancy. The purpose of this thesis is to find an anti-Wolbachia based treatment regimen that is suitable to be deployed in a community-directed MDA programme. Previous screening work carried out by the AWOL consortium on a clinically registered drug library, provided the list of potential anti-Wolbachia drug candidates by which this thesis intends to investigate (minocycline, rifampicin, rifapentine, moxifloxacin and fusidic acid). A series of PK/PD models where constructed using data derived from well-established screening protocols, using an in-vitro cell-based assays system in conjunction with a preclinical based in-vivo model using B. malayi infected SCID mice. The results published in this thesis demonstrate that high dose rifampicin (RIF) (30 mg/Kg qd) as well as elevated rifapentine (RIP) doses (7 mg/Kg qd) could be administered using a 7-day treatment timeframe and are able to deliver a greater than 90 % reduction in Wolbachia loads. This is comparable to the current anti-Wolbachia macrofilaricide ‘gold standard’ DOX, but without the protracted 4-6 weeks treatment period. Benefits of using a rifamycin based treatment regimen are its use in both children as well as pregnant women and it could be deployed in resource-poor communities by the current health care systems that are already in place, due to the shortened treatment timeframe required. In the case of fusidic acid (FA), although it didn’t achieve the 7-day target product profile (TPP), this is not unexpected as FA is notorious for its poor bioavailability across several different species. Also, moxifloxacin (MOXI) didn’t achieve the 7-day TPP further dose optimisation studies are needed to determine the optimum dose of (MOXI) required to deliver an anti-Wolbachia macrofilaricidal affect against LF and onchocerciasis. Although ABZ didn’t have any significant affect at reducing Wolbachia loads it has recently been demonstrated to provided synergistic effects when administered with anti-Wolbachia antibiotics. These findings presented in this thesis all warrant further clinical investigation to determine the clinical efficacy of delivering a 7-day treatment regimen to determine macrofilaricidal affects against LF and onchocerciasis.

Item Type:	Thesis (PhD)
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	13 Aug 2020 10:43
Last Modified:	19 Jan 2023 00:17
DOI:	10.17638/03064594
Supervisors:	Ward, Stephen Taylor, Mark
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3064594