Increased primaquine total dose prevents Plasmodium vivax relapses in patients with impaired CYP2D6 activity: report of three cases

Abstract

Background The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse. Cases presentation Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. Conclusion Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.

An increase in urinary primaquine and a reduction in urinary primaquine-5,6-orthoquinone in the Thai population with CYP2D6 reduced enzyme function

“…Our data also suggest that, for the treatment of malaria infection, an increase in the first primaquine dose may be beneficial and the CYP2D6 genetic-guided dose of primaquine should be further investigated. Studies also noted that if the first treatment failed without adjusting the first dose of primaquine, increasing the total dose of primaquine would be suggestive as a second-line treatment [ 10 , 29 ]. However, the acute hemolytic adverse effect related to primaquine must be closely monitored, especially if CYP2D6-metabolized drugs, such as codeine, dextromethorphan, metoprolol, nebivolol, and risperidone or CYP2D6 enzyme inhibitors, such as bupropion, fluoxetine, quinidine, and terbinafine, are co-administrated with primaquine [ 10 , 29 ].…”

Magic bullets, magic shields, and antimicrobials in between

“…Nitroxoline (8-hydroxy-5-nitroquinoline) is an 8-hydroxyquinoline derivative that has been prescribed as an antibiotic for decades in Europe to treat urinary tract infections, its antibiotic activity being attributed to its ability to chelate metal ions (akin to tetracyclines) and to dispel biofilms [ 54 ]. Chloroquine is a protonated, weakly basic 4-aminoquinoline that accumulates in the food vacuole of parasites and interferes with degradation of host red blood cell (RBC) haemoglobin, preventing malarial parasite growth [ [55] , [56] , [57] ]. Unmodified quinoline exhibits relatively high activity against some fungal strains at non-toxic concentrations and the fungistatic activity of 8-hydroxyquinoline and its metal complexes has been known since the early 1920s, with these compounds now broadly used in healthcare [ 58 ].…”

Plasmodium vivax: the potential obstacles it presents to malaria elimination and eradication

“…The currently WHO recommended treatment, people with P. vivax malaria should be treated with chloroquine for three days to kill the parasites that cause malaria symptoms in the blood, then 0.25 mg/kg of body weight (in a single daily dose) of PQ for 14 days to treat hypnozoite-derived relapses ('radical cure') of vivax malaria [ 118 ]. Based on a study conducted in Brazil by [ 50 ], the total dose given influences the radical curative efficacy so that compliance is essential for a radical treatment because effectiveness is correlated with the total PQ dose given. One of the clinical drawbacks of this treatment regimen is that it is more than four times longer than conventional schizontocidal regimens, which limits adherence to the lengthy regimen [ 118 , 162 ].…”

“…As a result, the CYP2D6 genetic polymorphism, which is very variable, may have an impact on the pharmacokinetics of primaquine [ 172 ]. False PQ tolerance assumptions in the parasite result from people with specific CYP2D6 polymorphism alleles being unable to metabolize PQ and possibly failing treatment [ 50 ]. It has been demonstrated in both animal models and people that primaquine's capacity to metabolize to its active metabolite is decreased by decreased CYP2D6 activity [ 156 ].…”