The Cardiovascular Toxicity of Antimalarial Drugs
Lead Research Organisation:
University of Oxford
Department Name: Clinical Medicine
Abstract
Malaria is an ancient mosquito-borne parasitic disease from which over a thousand - mostly children in sub-Saharan Africa - still die of needlessly every day. For half a millennium, quinine and quinine-like antimalarial drugs have been the mainstay of malaria treatment and prevention. In the 18th century, the chance observation of their ability to quell palpitations led to their becoming the first anti-arrhythmic agents. Some of these anti-arrhythmic antimalarials later came to define the adverse drug reaction of repolarisation-related cardiotoxicity as sudden deaths, ventricular tachyarrhythmias, and electrocardiographic QT interval prolongation were in turn causally associated with their use. With increasing population-level use of antimalarials for malaria elimination, there has been renewed global interest in defining the cardiovascular toxicity of key members of this drug class to guide antimalarial choice and dosage for development and deployment.
I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development through systematic reviews and meta-analyses of global data.
In particular, I assess the risk of:
1) Sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria
2) Torsade de pointes and other clinically significant arrhythmias after front-line antimalarials at standard malaria doses
I also evaluate the effects on the QT interval, the most commonly used surrogate marker for repolarisation-related cardiotoxicity risk, of:
3) Malaria disease, including severity and fever, which may account for differences in QT interval changes seen between healthy individuals and malaria patients
4) Amodiaquine, the quinoline antimalarial recommended by the WHO for seasonal malaria chemoprevention of millions of young children aged 3-59 months in the Sahel subregion of Africa as well as the treatment of uncomplicated malaria
I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development through systematic reviews and meta-analyses of global data.
In particular, I assess the risk of:
1) Sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria
2) Torsade de pointes and other clinically significant arrhythmias after front-line antimalarials at standard malaria doses
I also evaluate the effects on the QT interval, the most commonly used surrogate marker for repolarisation-related cardiotoxicity risk, of:
3) Malaria disease, including severity and fever, which may account for differences in QT interval changes seen between healthy individuals and malaria patients
4) Amodiaquine, the quinoline antimalarial recommended by the WHO for seasonal malaria chemoprevention of millions of young children aged 3-59 months in the Sahel subregion of Africa as well as the treatment of uncomplicated malaria
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013468/1 | 01/10/2016 | 30/09/2025 | |||
| 1790394 | Studentship | MR/N013468/1 | 01/10/2016 | 27/04/2019 | Xin Hui Chan |
| Guideline Title | HRS/EHRA/APHRS/LAHRS/ACC/AHA worldwide practice update for telehealth and arrhythmia monitoring during and after a pandemic |
| Description | Citation in COVID-19 clinical guidelines |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Citation in clinical guidelines |
| Description | Citation in malaria management review |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Citation in clinical reviews |
| Description | WHO ERG on the Cardiotoxicity of Antimalarials |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Presentation of report of WHO Evidence Review Group on the Cardiotoxicity of Antimalarials to WHO Malaria Policy Advisory Committee and WHO Advisory Committee on Safety of Medicinal Products. Addition of key antimalarial, the artemisinin-based combination therapy dihydroartemisinin-piperaquine, to WHO Essential Medicines List and WHO Essential Medicines List for Children. |
| URL | https://www.who.int/selection_medicines/committees/expert/21/applications/dihydroartemisinin_piperaq... |
| Description | Jill and Herbert Hunt Travelling Scholarship |
| Amount | £4,000 (GBP) |
| Organisation | University of Oxford |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 04/2016 |
| End | 04/2017 |
| Description | University of Oxford-Medical Research Council Doctoral Training Programme Supplementary Funding |
| Amount | £5,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2018 |
| End | 07/2019 |
| Description | University of Oxford-Medical Research Council Doctoral Training Programme Supplementary Funding |
| Amount | £3,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2017 |
| End | 07/2018 |
| Description | WHO Global Malaria Programme |
| Organisation | World Health Organization (WHO) |
| Department | Global Malaria Programme |
| Country | Switzerland |
| Sector | Charity/Non Profit |
| PI Contribution | Technical/scientific coordination of evidence review group on cardiovascular safety of antimalarial drugs |
| Collaborator Contribution | Overall coordination of evidence review group on cardiovascular safety of antimalarial drugs |
| Impact | A) Outputs: i) Technical report; ii) Technical presentations; iii) Peer-reviewed research articles. B) Multidisciplinary collaboration: i) Cardiology; ii) Clinical Malariology; iii) Clinical Pharmacology; iv) Drug Safety / Pharmacovigilance. |
| Start Year | 2016 |
| Title | MDA with DP + SLDPQ |
| Description | Medical intervention: Mass drug administration in peri-elimination settings with monthly dihydroartemisinin-piperaquine and single low-dose primaquine |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Late clinical evaluation |
| Year Development Stage Completed | 2017 |
| Development Status | Under active development/distribution |
| Clinical Trial? | Yes |
| Impact | Mapping of antimalarial drug resistance in the Greater Mekong Subregion |
| URL | https://clinicaltrials.gov/show/NCT01872702 |
| Title | TACT ALAQ & DPMQ |
| Description | Medical product: Triple artemisinin-based combination therapies of artemether-lumefantrine plus amodiaquine.and dihydroartemisinin-piperaquine plus mefloquine. Funder: Healthy volunteer studies - Bill and Melinda Gates Foundation; Malaria patient studies - UK Department for International Development. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Late clinical evaluation |
| Year Development Stage Completed | 2018 |
| Development Status | Under active development/distribution |
| Clinical Trial? | Yes |
| Impact | Mapping of antimalarial drug resistance in the Greater Mekong Subregion |
| URL | https://clinicaltrials.gov/show/NCT02453308 |
| Description | NDM Video Podcast |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Video podcast on research area publicised on websites and social media accounts of academic department, research network, research unit, and collaborators. |
| Year(s) Of Engagement Activity | 2018,2019 |
| URL | http://www.tropmedres.ac/xin-hui-chan-using-big-data-to-eliminate-malaria |