Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population

Abstract

Background Plasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite. Methods CYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry. Results Seventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype. Conclusion The plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure. Clinical Trials Registration NCT02960568.

<p>Pharmacogene Variation in Thai <em>Plasmodium vivax</em> Relapse Patients Treated with a Combination of Primaquine and Chloroquine</p>

“…These authors reported that patients with CYP2D6 activity scores of 1.0 or less had a higher risk of relapse compared to patients with scores >1.0 (OR=9.4, P=0.001). Another study conducted by Spring et al 30 confirmed that subjects with CYP2D6 IM or PM phenotypes have reduced PQ metabolism compared to those with an NM phenotype. In contrast, Chen et al 31 found that CYP2D6 phenotype or activity scores were not significantly different between their relapse and non-relapse groups.…”

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions

“…However, CYP2D6 activity measured with DEM may not be necessarily extrapolated to other CYP2D6 substrates, such as PQ ( Hicks et al, 2014 ). The recent demonstration that CYP2D6 polymorphisms affect the production of active phenolic metabolites of PQ represents a major advance in the field ( Spring et al, 2019 ). Reduced urinary levels of 5,6-ortho-quinone, a surrogate marker of the presumed active metabolite 5-hydroxyprimaquine, were measured in intermediate and poor metabolizers, consistent with the notion that CYP2D6-mediated biotransformation is essential for the therapeutic efficacy of PQ ( Spring et al, 2019 ).…”

Prevalence of CYP2D6 Genotypes and Predicted Phenotypes in a Cohort of Cambodians at High Risk for Infections with Plasmodium vivax

“…18 The IM-predicted phenotype encompasses a wide interval of activity scores (0.25-1), so an IM designation may not translate to equal risk for therapeutic failure. In a small pharmacokinetic (PK) study of PQ in healthy adults, PK parameters of IMs with AS-A of 0.25 (null allele/*10) were similar to PMs 19 ; thus, for our study in Cambodia, 7% of our population could potentially be at risk for PQ failure due to no/severely reduced CYP2D6 activity.…”

“…In field studies aiming to establish a relationship between CYP2D6 and radical cure failure, PK parameters of PQ (not measured in Study A) may be helpful. The plasma area under the curve (AUC) of PQ may not consistently predict efficacy, 2 , 18 but recently, 5,6-orthoquinone (5,6 OQ), the stable surrogate for unstable and presumed active metabolite, 5-hydroxyprimaquine, was measured in the urine of American adults of the NM predicted phenotype, 19 whereas the IM and PM subjects had very low levels or none. Prospective longitudinal studies of P. vivax infections and relapses, inclusive of CYP2D6 genotype/phenotype and PQ PK to measure 5,6 OQ and other metabolites, may provide useful information on the pharmacogenomic liabilities.…”