There are about 500 millions cases and about 2.7 million deaths from malaria each year.  Antimalarial drugs that are available are limited and the treatment is challenging due to the drug-resistance among the parasites.  Drugs such as quinine, chloroquine (CQ) and mefloquine have been used in treatment for controlling malaria.  However, due to drug-resistance and treatment failure, combination therapy has been proposed.  It is thought that the mechanism of action of these compounds is the inhibition of the parasite within infected erythrocytes [1].

Amodiaquine (AQ) is not generally prescribed for uncomplicated malaria due to toxicity.  CQ is the firstline therapy.  The severe adverse drug reaction (ADRs) associated with AQ is the agranulocytosis which affects 1 in 2000 patients and severe neutropenia which affects 1 in 2100 patients.  

Amodiaquine (AQ) is an antimalarial drug that may be a potential candidate for the combination therapy and due to its low cost can be used as a therapy in Africa.  AQ may have better parasite clearance and faster recovery than CQ.  CQ was shown to have treatment failure within 4 weeks in about 60% of the follow ups [2, 3].  Studies have shown that AQ is almost entirely metabolized by CYP2C8.  Variants of the enzyme have shown to decrease activity of the enzyme and may pose a problem for AQ metabolism and cause accumulation of the drug and subsequent toxicity.  Due to ADRs the use of AQ has declined [2].

There are racial differences in the frequency of CYP2C8 variants.  The *2 allele is associated with decreased activity of the enzyme.  This polymorphism has a higher allele frequency of 0.18 in the African American population, 0.139 in the Sub-Saharan African population and 0.168 in Ghana while it is lower in Caucasians (0.016) and Malay (0.035) [2].  This suggests that African Americans are expected to have a higher incidence of developing ADRs.   This variant (CYP2C8*2) is expected to have an increased susceptibility to ADRs.  

Proposal:

In Ghana and East Africa, the control of malaria is approaching a crisis as CQ is failing as a firstline therapy.  Thus, AQ an affordable and efficacious antimalarial would be beneficial to be used as a firstline therapy.  I propose that we carry out that we genotype individuals in Africa for the CYP2C8*2 variant prior to therapy.  We would then prescribe AQ for those individuals that screen negative for this variant. We would also need to have a control group where we prescribe AQ to all individuals and genotype these individuals after treatment.  Therefore by genotyping the African population prior to therapy will reduce the incidence of the severe ADRs by determining the appropriate therapeutic dose/alternative drug according to the CYP2C8 variants.   We must also carry out a cost-benefit analysis to determine whether genotyping individuals will truly benefit patients in Africa.

References:
1.Thompson AJ et al (2007) British Journal of Pharmacology.  151:  666-677.
2.Susanne R et al (2005) Tropical Medicine and International Health. 10:  1271-1273.
3.Gil JP, Berglund GE. (2007) Pharmacogenomics. 8: 187-198.