Investigating the pharmacology and mechanism of action of 8-aminoquinolines against liver stage malaria parasites.

Jinks, Jessica (2024) Investigating the pharmacology and mechanism of action of 8-aminoquinolines against liver stage malaria parasites., Thesis (Doctoral), Liverpool School of Tropical Medicine.

Text J Jinks_Thesis_2024.pdf - Accepted Version Restricted to Repository staff only until 31 July 2029. Download (25MB)

Abstract

The 8-aminoquinolines are the only licenced class for the treatment of relapsing malaria. Key members of the class include currently licenced compounds: primaquine and tafenoquine; as well as legacy compounds: pamaquine and pentaquine. Presented by Camarda et al., (2019), the current hypothesised mode of action for primaquine comprises a 2-step biochemical relay: (1) CYP-mediated (predominantly CYP 2D6) metabolism into reactive intermediates; and (2) redox cycling of metabolites with Cytochrome P450 (CYP) reductase (CPR) to form anti-parasitic levels of Reactive Oxygen Species (ROS). This thesis has investigated whether this mechanism of action is class-wide, scrutinising both CYP-mediated metabolism of the 8-aminoquinolines, and 8-aminoquinoline-mediated ROS production. This thesis presents a thorough exploration into the physicochemical and drug metabolism/pharmacokinetic (DMPK) properties of 8-aminoquinolines and key clinically relevant combination partners. Key DMPK analyses include hepatic metabolism with HµREL® co-culture clearance assay and investigations into CYP-specific metabolism, inhibition, and induction. Physiologically-based pharmacokinetic (PBPK) modelling has been utilised to clinically contextualise this data. Ongoing and preliminary data into the pharmacodynamicmechanisms of 8-aminoquinolines includes the measurement of CYP-mediated ROS using Pan-CYP and CYP-specific inhibitors and measures of cellular oxidative stress including Haem Oxygenase-1 and nuclear factor erythroid 2–related factor 2, as well as experimentation into in vitro efficacy using a Plasmodium cynomolgi liver stage assay. This thesis presents new evidence for the idea of a divergent bioactivation step (1), and convergent ROS-mediated step (2) in the mechanism of action across the 8-aminoquinoline class, with tafenoquine not showing hepatic metabolism or CYP-mediated ROS production. Tafenoquine licencing now requires compulsory co-administration with chloroquine due to treatment failure with alternative regimen, piperaquine-dihydroartemisinin. Data collected within this thesis suggests that these drug-drug interactions (DDI) are unlikely to be CYP-mediated for both primaquine and tafenoquine. Preliminary research points to the DDI occurring at the step 2 of the hypothesised mechanism of action. Further research is required to confirm the potentiating effect of chloroquine, and inhibitory effect of dihydroartemisinin on the redox-related efficacy of 8-aminoquinoline agents.

Item Type:	Thesis (Doctoral)
Subjects:	QV Pharmacology > QV 4 General works QX Parasitology > QX 20 Research (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	31 Jul 2024 11:09
Last Modified:	31 Jul 2024 11:19
URI:	https://archive.lstmed.ac.uk/id/eprint/25033

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