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Translational potential

Work by Clinical Pharmacology has led to a number of potentially new therapeutics interventions being uncovered, including:

  • Use of triple artemisinin combination therapies to prevent the emergence and spread of drug resistant malaria. A large multicentre multi-country trial (TRAC II) finished recruiting in 2018, and preliminary results show that they are reasonably well tolerated and effective against multi-drug resistant malaria;
  • The RTS,S malaria vaccine provides short term drug-independent protection against falciparum malaria, and may be a useful tool for malaria elimination campaigns. We have assessed for the first time the immunogenicity of RTS,S in Asian adults, and whether concomitant dihydroartemisinin-piperaquine affects it. These studies have now been completed and show good immunogenicity, no significant interactions, and they inform appropriate dosing;
  • Dihydroartemisinin-piperaquine was evaluated as seasonal chemoprevention in young children in Burkina Faso. Our Clinical Pharmacology Department conducted the bioanalysis and described the PK/PD properties of piperaquine using modelling and simulation, showing that young children need a relatively higher dosage compared to adults. Increased piperaquine dosage and extended coverage during the high transmission season could have a substantial impact on the incidence of malaria;
  • The renoprotective effects of paracetamol were evaluated in patients with severe and moderately severe falciparum malaria in a randomised, controlled, open-label trial. The pharmacokinetic-pharmacodynamic analysis showed that higher exposure to paracetamol increased the probability of creatinine improvement, and therefore, a renoprotective effect of paracetamol;
  • 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 within the pharmacology department;
  • Primaquine is widely recommended but often not used. We have calculated the proportions of patients unable to receive the new 8-aminoquinoline tafenoquine and thereby shown that primaquine will still be necessary if tafenoquine is introduced for the radical cure of vivax malaria. 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.
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