Estimating antimalarial drug activity in vivo: an interdisciplinary approach combing novel experimental data with mathematical modelling

Malaria infections led to an estimated 627 000 deaths in 2020. Artemisinin-based combination therapies are the current first-line malaria treatments. However, it is urgent to develop better antimalarial because artemisinin-resistant parasites are spreading, and the international efforts to eradicate malaria have stalled. There are currently 46 drugs in development by the Medicines for Malaria Venture at different phases of the drug development pipeline. During development, antimalarial drugs are tested in pre-clinical animal models and early-stage clinical trials to determine in vivo drug activity and safety. In these early phases, the criteria used to assess a candidate antimalarial drug's activity in vivo is the rapid clearance of parasites from the peripheral circulation called 'parasite clearance'. Short parasite clearance half-lives are interpreted to mean rapid drug action. These parasite clearance data are used to parameterise PK/PD models that relate the drug's concentration with its killing activity in vivo. These models are used to predict and optimise dosing strategies for later clinical trials. However, it has recently been demonstrated that parasite clearance does not reflect how fast a drug kills parasites. The use of parasite clearance as a metric for assessing candidate antimalarial drugs must be revisited. Here, I consider novel parasite viability data from humanised mice and humans treated with two antimalarial drugs to develop a model of antimalarial drug activity and build a more nuanced understanding of parasite killing and host removal of dead parasites. The new assay we use for estimating parasite viability is highly sensitive and can quantify down to one viable parasite per blood sample. Considering these parasites' viability estimates - rather than simply measuring parasite clearance - results in a more consistent PK/PD model that can better explain the parasite recrudescence after treatment. Moreover, the parasite-killing half-life is more sensitive to drug exposure time, dose and treatment regimen than the parasite clearance half-life. In vivo drug activity estimates determine which antimalarial drug candidates will proceed down the development pipeline. My work shows that considering parasite viability increases PK/PD models' accuracy in explaining drug activity. Such models will provide a more precise measure of drug efficacy and can be used to assist in identifying the best treatment amongst the possible antimalarial candidates.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2022

Author dc:creator

• Randriafanomezantsoa Radohery, Georges

• Plasmodium falciparum
• antimicrobial activity
• artesunate
• clinical trials
• drug activity
• malaria
• preclinical drug studies
• viability
• Controlled Human Malaria Infection
• anzsrc-for: 320704 Medical parasitology
• anzsrc-for: 321402 Clinical pharmacology and therapeutics

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/24186

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/100479