Integrated Experimental and Computational Approaches for the Prediction of Drug-Drug Interactions

Kinvig, Hannah
(2021) Integrated Experimental and Computational Approaches for the Prediction of Drug-Drug Interactions. PhD thesis, University of Liverpool.

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People living with HIV (PLWH) are highly susceptible to drug-drug interactions (DDIs) due to the increased risk of coinfections and comorbidities. Antiretroviral (ARV) drugs used for the treatment of HIV can be both victims and perpetrators of DDIs with potential effects on drug exposure leading to reduced efficacy and toxicity. Transporters have been identified as key mediators of drug pharmacokinetics however their role in DDIs remains unclear due to our current paucity of knowledge. The complexities surrounding the clinical management of DDIs in PLWH is further hindered by a lack of evidence-based guidance for many drug combinations. The aim of this thesis was to utilise in vitro and in silico techniques to explore the role of transporters in DDIs as well as investigate the magnitude of potential DDIs in PLWH that currently have no clinical data to support their management. Uptake and efflux transporters facilitate the clearance of drugs in the liver however, due to the complex interplay with enzymes along with non-specific probe substrates and inhibitors, their role in clinically relevant DDIs have not been fully elucidated. In vitro and in silico techniques can be applied synergistically to investigate hepatic transporter-mediated DDIs. Chapter 2 describes the development and verification of a cryopreserved suspension primary human hepatocyte (SPHH) in vitro assay used to calculate the hepatic intrinsic clearance and inhibition constant (Ki) of the well-known organic anion transporting polypeptides (OATP) 1B1 and 1B3 substrate and inhibitor, pitavastatin (PIT) and rifampicin (RIF). This in vitro data was then utilised in Chapter 3 in a physiologically based pharmacokinetic (PBPK) model to simulate the DDI between PIT and RIF and was successfully verified against observed data. Chapter 4 applied the verified in vitro-in silico framework to assess the role of transporters in the complex DDI between the hepatitis C (HCV) NS3/4A protease inhibitor (PI) grazoprevir (GZR) and HIV PIs atazanavir (ATV), darunavir (DRV) and ritonavir (RTV), testing the suitability of the framework in a clinically relevant DDI scenario. Additionally, chapter 5 utilised SPHHs from elderly donors in vitro alongside an enzyme-linked immunosorbent assay (ELISA) to investigate the effect of age on transporter expression and activity. Furthermore, in chapter 6 an enzyme induction PBPK model was developed and verified to predict the magnitude of DDI between high dose once monthly (QMT) RIF and dolutegravir (DTG) 50mg twice-daily for the treatment of leprosy in PLWH as there is currently no evidence-based guidance to support their clinical management. There is a demand for paralleled clinical management and research of DDIs in PLWH. These findings represent a potential in vitro-in silico framework utilising a non-drug specific IVIVE correction factor for the investigation of hepatic uptake transporters in DDIs. Additionally, these findings could help fill the knowledge gap on the role of older age in transporter expression and activity, providing key research in this underrepresented population. The reported findings could also help support the clinical management of DDIs in high dose QMT RIF regimens, presenting in silico assessment strategies for concomitant antiretroviral therapy.

Item Type: Thesis (PhD)
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 01 Oct 2021 14:54
Last Modified: 06 Jan 2022 08:17
DOI: 10.17638/03135423