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P2 purinoceptors comprise ionotropic (P2X) and metabotropic (P2Y) receptor families, responsive to nucleotide ligands and diversely distributed on virtually every mammalian cell. Most cells and tissues co-express multiple subtypes of purinoceptor; thus, unraveling the functional role – and pharmacological potential – of any subtype is a complex task. Additionally limiting is the paucity of potent, selective antagonists, particularly those with suitable physicochemical and pharmacokinetic properties for animals models and clinical development. These studies address questions initially debated >10 years ago, following the successful cloning of purinoceptor families. First, given the large, polyanionic or nucleotide chemical probes available for pharmacology, are these receptors medicinally tractable? Secondly, given the admixture of purinoceptor expression in mammalian cells, would selective interference impact pathophysiology and disease burden; or would redundancy dominate? Through the current investigations some answers can be offered. First, a resounding “yes”, second, a more equivocal “possibly”. Importantly, in addressing these queries, our investigations – and others - have furnished both important data on biological relevance of P2 subtype expression and function, as well as excellent chemical and biological tools for future investigators, so that more answers can be found. Meanwhile, the pharmacological characteristics of two novel prototype antagonists have been detailed: for P2X1 (RO-1) and P2X3-containing receptors (RO-4). Additionally, the potential value of these compounds for the study of P2X signaling in vitro and in vivo, as well as templates for candidate medicines with a wide variety of potential therapeutic uses are demonstrated. It has also been possible to elucidate the potential of selective interference in certain target tissues – urological and sensory – and increasing the apparent therapeutic potential. We can indeed conclude that P2X channels of focus in this work, P2X1, P2X3 and P2X2/3, are druggable; the true therapeutic value of antagonists of these channels is awaited.

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Antiretrovirals (ARVs) can find clinical application for both treatment and prevention of HIV infection. Pre-exposure prophylaxis (PrEP) strategies have been recently introduced to protect individuals who are at high risk of acquiring HIV infection. The majority of existing ARVs are oral formulations which necessitate lifelong daily dosing and suboptimal adherence to this dosing regimen could result in development of viral resistance against treatment. Long-acting injectable (LAI) nanoformulations administered either intramuscularly or subcutaneously could be a valuable pharmacological option. LAIs could potentially simplify dosing regimen, reducing the total amount of drug consumed thus reducing the oral cost of treatment/PrEP and most importantly addressing the problem of suboptimal adherence. The development of novel LAI therapies is complicated by several pharmacological factors including ARV pharmacokinetics and compatibility with existing formulation strategies. The overall aim of this thesis was to investigate and simulate the pharmacokinetics of LAI formulations in order to provide effective tools to inform the future development of formulations. A number of different strategies to investigate the pharmacokinetics of LAI formulations were developed in this thesis. Physiologically based pharmacokinetic (PBPK) modelling represents the mathematical description of anatomical, physiological and molecular processes that define pharmacokinetics in humans. In the recent past, PBPK models have been developed for several disease areas to simulate pharmacokinetics in humans, which currently play an active role in the design of clinical trials and regulatory approvals. In Chapter 2, human adult PBPK models have been developed and validated against clinically available pharmacokinetic data of oral formulations for eight ARVs. These validated models were then used to identify theoretical optimal dose and release rates of LAI formulations for weekly and monthly administration. Clinical studies in paediatric patients encounters ethical issues and possesses concerns during dose optimization. In Chapter 3 and 4, PBPK models have been developed and validated for children and adolescents for existing LAI formulations of cabotegravir and rilpivirine. Doses were optimised for monthly administration such that the plasma concentrations stay over the assumed target concentrations, for paediatric population according to different weight groups recommended by World Health Organisation. In Chapter 5, experimental methods (static release dialysis, sample-and-separate method and dynamic release dialysis) to evaluate the drug release rate from the site of injection were developed. The in vitro release rates were correlated with clinical release rates to obtain a mathematical equation describing the in vitro in vivo extrapolation (IVIVE) in Chapter 6. Novel computational and experimental methods to support the development and optimisation of LAI formulations are required. These findings represent valuable applications of novel methods to simulate and characterise the pharmacology of LAI formulations. The reported findings could help simplify ARV dosing strategies by providing an initial dosing guideline for clinical trials in humans. This approach could improve therapy thus addressing the problem of suboptimal adherence and reduce cost of overall treatment. PBPK models and IVIVE could be an innovative strategy to evaluate drug pharmacokinetics in humans and optimise dose and release rates of novel formulations for LAI HIV therapy.