Informing optimal dosing of the future antimalarial, artemether-lumefantrine plus amodiaquine, in key neglected target populations of children with severe acute malnutrition and adults living with HIV

PROJECT SUMMARY/ABSTRACT This award will allow Dr Clifford George Banda to characterise the pharmacokinetic and safety profiles of two long-acting artemisinin partner drugs, lumefantrine and amodiaquine and their active metabolites when administered as artemether-lumefantrine plus amodiaquine (ALAQ) in African young children with uncomplicated severe acute malnutrition

as well as adults living with HIV and on dolutegravir-based antiretroviral therapy. Dr Banda, Malawi’s first medical specialist in Clinical Pharmacology and Therapeutics, will further his career development by;1) gaining skills in early phase clinical trial design and conduct in complex subpopulations; 2) consolidating skills in clinical translation of quantitative

pharmacology (population pharmacokinetic-pharmacodynamic modelling) to inform dose optimisation of antimalarials in the two key target subgroups of children with severe acute malnutrition and adults living with HIV; and 3) strengthening his clinical and research leadership skills to allow transition into research career independence. In the proposed

project work,he hypothesises that severe acute malnutrition is associated with reduced absorption and subsequent bioavailability of lumefantrine, amodiaquine and their active metabolites. Consequently, the attained concentrations would be insufficient to treat and prevent malaria recurrence. He will study the effect of uncomplicated severe acute

malnutrition on lumefantrine and amodiaquine exposure. Furthermore, there are concerns about a potential reduction of dolutegravir exposure when amodiaquine is co-administered with dolutegravir-based antiretroviral therapy, Dr Banda will characterise the effect of ALAQ on dolutegravir overall exposure in adults living with HIV. This evidence is needed to inform

the optimal dosing of the promising triple antimalarial combination, ALAQ, in these two subpopulations. It would support the World Health Organisation’s strategy for responding to antimalarial resistance in Africa by identifying innovative ways to combine and repurpose existing antimalarial therapies as a tool to delay antimalarial resistance while awaiting the

development and licensing of novel non-artemisinin-based combination therapies.