Bunglawala, Fazila
(2022)
Exploring the Applications of PBPK Modelling to Optimise HIV-1 Treatment.
PhD thesis, University of Liverpool.
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Abstract
Human immunodeficiency virus (HIV-1) infection continues to be a significant public health concern, with 36.3 million lives being claimed by the infection thus far. Currently there is no cure for HIV. Antiretroviral (ARV) therapy has considerably increased life expectancy in people living with HIV (PLWH), however, several challenges remain. This thesis investigates the various ways in which physiologically based pharmacokinetic (PBPK) modelling can be developed and applied with the aim of optimising treatment for human immunodeficiency virus (HIV-1) infection. Neonatal patients are considered a vulnerable population as limited clinical studies are conducted in this population. Newborns born to mothers with HIV are at risk of receiving HIV. Lack of pharmacokinetic (PK) data means fewer treatment options are available. Chapters 2 & 3 focus on developing and applying a neonatal PBPK model to investigate the PK of integrase inhibitors, dolutegravir and bictegravir in neonates. Chapter 4 goes on to describe how modelling can be used to predict the PK of novel formulations by simulating long-acting, intramuscular, cabotegravir in neonates. Polypharmacy is routinely observed in PLWH, and drug-drug interactions (DDIs) prove an obstacle in HIV treatment, Chapter 5 involved developing an adult PBPK model to evaluate the magnitude of moderate inducers on novel ARVs. Residual levels of viraemia hinder the ability to develop a cure, Chapter 6 investigated the penetration of ARV drugs in lymphoid tissues using a mechanistic lymphatic PBPK model. Understanding the penetration of drugs in target tissues can help optimise ARV therapy. Collectively, this thesis evaluates the possible ways HIV treatment can be improved and optimised by investigating the potential of treatments in special populations, novel formulations of ARV drugs, management of drug-drug interactions and the penetration of therapy in target tissues.
| Item Type: | Thesis (PhD) |
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| Divisions: | Faculty of Health and Life Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 21 Nov 2022 11:45 |
| Last Modified: | 18 Jan 2023 19:43 |
| DOI: | 10.17638/03166219 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3166219 |
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