Malaria infects over 1 million Indonesians yearly, dominated and represented equally by both Plasmodium falciparum and Plasmodium vivax (species of parasites that cause malaria in humans). Vivax malaria requires treatment with blood schizontocides (anti-malaria drugs) to arrest the patent attack and with hypnozoitocide to kill the dormant hepatic forms of latency.
The only available hypnozoitocides are the 8-aminoquinoline drugs primaquine and tafenoquine. In 2018, we reported an association between impaired host CYP2D6 activity and the therapeutic efficacy of high-dose, directly supervised primaquine therapy against relapse of P. vivax during a randomised clinical trial. In brief, 20 of the 21 treatment failures examined for CYP2D6 genotype and CYP2D6-mediated metabolism of dextromethorphan phenotype showed significantly impaired activity.
All of this work followed the findings of Bennett et al. (NEJM 2015), where 2 of 25 experimentally challenged volunteers in the USA experienced multiple treatment failures of primaquine and had impaired CYP2D6 genotypes. Primaquine thus appears to be a prodrug metabolised by CYP2D6 to its active therapeutic form, long suspected to be a 5-hydroxy-quinonimine species (5HQ). Natural polymorphisms in CYP2D6 directly impact the therapeutic efficacy of primaquine for the radical cure of vivax malaria. The 5HQ metabolite of primaquine is highly unstable and nearly impossible to detect directly. Recent work has identified a stable derivative of it – 5,6-orthoquinone (5,6OQ) – in urine between 3 and 6 hours after dosing.
In the PRIMA trial, 49 subjects dosed with daily primaquine were admitted to the clinic for a 72-hour period. We collected urine samples over that period at intervals intended to identify the optimal hour of post-primaquine dosing for urine analysis. All of these samples are archived and will undergo LC/MS analysis in late 2022.
