Antimalarial drug levels in biological samples: methods and applications.

Abstract

This thesis deals with the development and validation of analytical methods that are field-adapted and their application in the determination of antimalarial drug levels in biological samples. These methods are suitable in countries where resources are limited. Usually studies about malaria are done in remote areas where access to basic facilities such as power is limited. Under such circumstances, methods which required refrigeration of samples cannot be applied. High performance liquid chromatographic methods have been applied for the quantitative determination of the drugs and their metabolites which has enabled most of the methods used/ developed to be sensitive and specific with low limits of detection. The determination of antimalarial drugs in biological samples from Ugandan healthy volunteers and patients is discussed. Attention has been drawn to some antimalatial drugs (Chloroquine, sulfadoxine and pyrimethamine amodiaquine and lumefantrine) that are used for the treatment of malaria in Uganda. Earlier published analytical methods have been optimised and used to determine the drug levels in plasma obtained from healthy volunteers. The results have been used to assess the bioavailability of chloroquine, sulfadoxine and pyrimethamine in a locally manufactured fixed-dose formulation (HOMAPAK). The efficacy and safety as well as aspects of their pharmacokinetics have been discussed. Field adapted analytical methods for determining therapeutic levels of amodiaquine, lumefantrine and their metabolites from whole blood, dried on filter papers have been developed and validated. Both amodiaquinine and lumefantrine had previously been reported to be very unstable on filter paper and rapidly degraded at room temperature. The field-adapted methods came into mind after the national antimalarial drug policy was changed from SP/CQ to coartem, a co-formulation of artemether and lumefantric. Amodiaquine plus artesunate is the alternative first line treatment for uncomplicated malaria in Uganda. Lastly, The method developed for quantification of amodiaquine and its metabolite, DAQ has been applied in the field to explore the practical applicability of the sampling procedure and its sensitivity. Blood collected from pediatric malaria patients on treatment form amodiaquine plus artesunate (AQ=AS) has been analysed for drug levels. A discussion of parasite clearance in relation to the attained drug levels has been given. In conclusion, new fielded adapted methods suitable for use in malaria endemic and resource poor countries have been developed. The methods will serve as a useful tool for future population based studies involving the use of amodiaquine and lumefantrine.