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Project Topic
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Global targets to reduce mortality from HIV infection will not be attained without a specific focus on populations who are often excluded from clinical trials. This is exemplified by unanswered questions surrounding management of tuberculosis (TB) in individuals on second-line anti- retroviral therapy (ART), including pregnant women, children and adolescents. TB remains the leading cause of HIV-related deaths. Despite normalisation of CD4 counts on ART, incidence remains 4-fold higher than in the HIV-uninfected population. Current WHO-recommended second-line ART contains boosted protease inhibitors (bPI). Significant drug-drug-interactions (DDI) between the key anti-TB drug rifampicin (RIF) and bPIs preclude the use of bPIs at standard doses. Lack of data informing dosing of the better-tolerated bPI regimens in patients requiring TB treatment is a significant barrier to their use in lowresource settings. Focussing on this priority research area, we will integrate computational approaches for prediction of DDIs with focussed clinical studies, describing exposure variability in vulnerable populations. Improving current understanding of drug disposition in complex clinical scenarios and providing a flexible platform for identifying clinical strategies with application across several disease areas will have wide-ranging impact in the management of poverty related diseases in special populations. Physiologically-based pharmacokinetic (PBPK) modelling will be developed to understand bPI and RIF DDIs, identifying potential dosing strategies to overcome these in adults and special populations (WP1). Data will inform clinical pharmacokinetic studies exploring the necessary dose escalation of boosted atazanavir, including in the context of high-dose RIF, performed in Kampala (WP2). Intracellular pharmacokinetics will further characterise the DDI (WP3). PBPK and population pharmacokinetic (pop-PK) modelling will be integrated enabling extrapolation to special populations (WP4), and sparse data from such populations receiving different combinations of second-line ART and/or TB treatment in Kampala and Cape Town will validate and refine these models (WP5). Capacity building focussing on equipping African scientists with the tools to efficiently define drug dosing in complex populations (WP6), communication and stakeholder engagement (WP7) will increase the application of this methodology to other priority research into pharmacokinetics in special populations. The research consortium comprises: Department of Molecular and Clinical Pharmacology, University of Liverpool (UoL), United Kingdom: Prime Organisation co-ordinating project; Joint Clinical Research Centre (JCRC), Kampala, Uganda; Infectious Diseases Institute (IDI), Makerere University College of Health Sciences (Mak-CHS), Kampala, Uganda; Division of Clinical Pharmacology, University of Cape Town (UCT), South Africa; Clinica Universitaria di Malattie Infettive, Ospedale Amedeo di Savoia, University of Turin, Italy.
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