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CTU has conducted pharmacokinetic studies on antimalarial drugs, anti-influenza drugs, antitrypanosomal drugs, endectocides, and the RTS,S malaria vaccine in Thai adults as a prelude to a malaria elimination evaluation. It is currently evaluating an ascending dose regimen for primaquine in G6PD deficiency.

Moru mosquito 2019 0064 © 2019 MORU. Photographer: Gerhard Jørén
Members of CTU’s clinical team with a volunteer.

A particular feature of antimalarial drug studies is the need for protracted follow-up because many of these drugs are very slowly eliminated. Wash out periods of months are required in crossover studies. These studies, mainly designed to optimise dosing, have underpinned large clinical trials conducted by MORU and partners.

CTU’s significant achievements include work in healthy volunteer studies and analysis:

Antimalarial drug interaction studies | Cardiovascular toxicity of the antimalarial drugs | Ivermectin | Vaccines | Development of a new primaquine radical cure regimen | Pharmacokinetic equivalence study of a new parenteral artesunate formulation | Analysis

Antimalarial drug interaction studies

An ongoing series of studies is assessing the pharmacokinetics and safety of triple artemisinin combinations (TACTs). The most important finding to date – which allowed the multinational clinical trials to proceed – was to show that mefloquine did not potentiate the effects of piperaquine on ventricular repolarisation. An assessment of the interaction between artemether-lumefantrine and amodiaquine is in progress. 

Cardiovascular toxicity of the antimalarial drugs

In collaboration with WWARN and in association with WHO an extensive review of antimalarial toxicity has been completed, focussing on DHA-piperaquine initially (and showing safety), and now extending to other antimalarial drugs.

The effects of malaria and fever on the ECG have been characterised and approaches for rate correction for the QT interval assessed based on the largest available databases.

Ivermectin

A comprehensive pharmacokinetic-pharmacodynamic evaluation of the endectocide ivermectin has shown that mosquitocidal effects persist beyond the elimination of the predominant component of the parent compound. This opens up the possibility of either an unidentified active metabolite, or slower elimination of the more active minor component. In either case this has firmly put ivermectin in centre stage as a potential elimination tool. WHO has endorsed this and encouraged further research to identify the active principals - which is ongoing with the Department of Pharmacology.

Vaccines

Another elimination option is to use the RTS,S malaria vaccine, which provides short term drug-independent protection against falciparum malaria. We have assessed for the first time the immunogenicity of RTS,S in Asian adults, and we also need to establish whether concomitant dihydroartemisinin-piperaquine affects it. These studies have now been completed and show good immunogenicity, no significant interactions, and they inform appropriate dosing.

Development of a new primaquine radical cure regimen

Primaquine is widely recommended but often not used. We have shown, using a new approach combining genotyping and time to event modelling, that if primaquine is used properly it can prevent nearly all relapses. This currently requires testing for G6PD deficiency and this is relatively expensive and generally unavailable. We have modelled an ascending dose regimen that should avoid dangerous haemolytic toxicity and could therefore be used without G6PD testing. This regimen is being tested in an adaptive trial design in known G6PD deficient healthy volunteers.

Pharmacokinetic equivalence study of a new parenteral artesunate formulation

The largest ever volunteer pharmacokinetic study of artesunate was completed which evaluated a new simplified parenteral artesunate formulation. This was successfully completed and confirmed bioequivalence.

Analysis

The analytical team have:

  • Shown that collider bias may explain recent high-profile claims that G6PD deficiency may
  • protect against cerebral malaria directly.
  • Using causal inference theory based on directed acyclic graphs that moderate anaemia protects against mortality in patients with severe malaria.
  • Developed a new approach to the interpretation of P. vivax recurrences that combines genotyping and time to event modelling, and allocates the cause of recurrence with a high degree of confidence.
  • Modelled the pharmacokinetic-pharmacodynamic relationships underlying toxicity of the newly registered sleeping sickness medicine fexinidazole. This was important in contributing to EMA approval in October 2018.