Responsible investigator:  Prof. J. Kevin Baird

Investigators:

Funded by Medicines for Malaria Venture

 

Scientific background

 

Preliminary data suggest there may be a relationship between CYP2D6 activity and primaquine anti-relapse efficacy. In a small cohort, subjects who had low activity phenotype of CYP2D6 had reduced primaquine efficacy compared to subjects who were extensive metabolisers. It has been hypothesised that polymorphisms in CYP2D6 may decrease formation of an active metabolite of primaquine resulting in increased risk of relapse. The relationship between CYP2D6 genotype and risk of P. vivax will be explored in this study.

 

There are more than 100 variants of the polymorphic CYP2D6 gene. The prevalence of poor metabolizers in Australia is estimated to be approximately 3%. In parts of Africa, the prevalence is higher. On the other hand, although the prevalence for variants encoding CYP2D6 poor metabolizer phenotype in Malaysians appears to be low (0 for CYP2D6*3, 0.028 for CYP2D6*4, 0.051 for CYP2D6*5), the prevalence for CYP2D6*10, which encodes intermediate metabolizer status, is relatively high at 0.49 (Sistonen et al. 2007). In an Indonesian study in which limited CYP2D6 variants were assayed, the estimate of metabolizer phenotype prevalences were 0 for null, 33 for intermediate, 60 for extensive, and 0 for ultra metabolizer  (Perwitasari et al. 2011). There are multiple test systems available to determine the genotype of an individual. In some regions of the world, genotype alone is sufficient to extrapolate to CYP2D6 phenotype status (poor, intermediate, normal, or ultra metabolizer). However, outside of North America and Europe, the extrapolation of genotype can less accurately predict phenotype (Dodgen et al. 2013). In circumstances where CYP2D6 phenotype needs to be established, a probe CYP2D6 substrate is administered to a subject and blood and urine samples are obtained serially over time to determine the pharmacokinetics of parent and metabolite in order to determine the ratio of parent to metabolite. In this way, CYP2D6 phenotype can be established.

 

Objectives

 

This case-control study will examine the frequency of fast-intermediate-slow CYP2D6 metabolism of a single dose of dextromethorphan among patients who relapsed after directly observed primaquine therapy compared to those who did not relapse. Secondary objectives are to compare the CYP2D6 phenotype with CYP2D6 genotype, to compare primaquine pharmacokinetics by phenotype and genotype status.

 

Hyphotesis

 

This study will investigate the association of CYP2D6 and vivax malaria relapse. Several evidences support the hypothesis that CYP2D6 is necessary to convert primaquine to a more active metabolite for efficacy. However, a recent case report of a patient who relapsed following chloroquine and primaquine treatment for Plasmodium vivax was recently published (Bright et al. 2013). The patient was genotyped for CYP2D6 and found to be WT/WT and, therefore, considered to have a normal CYP2D6 phenotype. The patient relapsed at least 3 times despite directly observed treatment with chloroquine and primaquine. These findings are not consistent with the hypothesis that those who relapse following adequate antimalarial treatment are CYP2D6 deficient.

 

Potential significance

 

Since 26 of 180 patients treated with primaquine relapsed in Study OXTREC 179-12 to date, it is important to understand whether these subjects were CYP2D6 poor- or possibly intermediate-metabolizers. Individuals who participated in the relapse-prevention Study OXTREC 179-12and who provided informed consent will be genotyped. Those individuals who relapsed will be asked to participate in a case control study to determine CYP2D6 phenotype by taking a single dose administration of dextromethorphan. A cohort of non-relapsed subjects will be recruited as controls for comparison purposes. Subjects who provide informed consent and who meet inclusion criteria and not exclusion criteria will be recruited to this study.

Related unit(s):

Coordinator: John Kevin Baird