Introduction

Primaquine is a potent antimalarial medication indicated for the radical cure of malaria caused by Plasmodium vivax (P. vivax) and Plasmodium ovale (P. ovale) species (1, 2). Malaria is a blood borne infection caused by infection of Plasmodium parasites that is spread by mosquitos. The P. vivax and P. ovale species present a particular challenge to treat because the parasitic life cycle includes a dormant, liver-specific stage that is not susceptible to other antimalarial medications. Thus, primaquine is often used with other therapies such as chloroquine or artemisinin-based medicines that target the reproductive, active forms of the parasite. Primaquine is also used to prevent transmission of malaria caused by Plasmodium falciparum (P. falciparum) species. A single, low dose (SLD) of primaquine has gametocidal activity, which does not cure the individual but does provide malaria transmission control.

Primaquine is a pro-drug that must be activated by the cytochrome P450 (CYP) enzyme system. Metabolism by the cytochrome P450 member 2D6 (CYP2D6) and cytochrome P450 nicotinamide adenine dinucleotide phosphate (NADPH):oxidoreductase (CPR) generates 2 hydroxylated active metabolites that generate hydrogen peroxide (H₂O₂). This causes significant oxidative stress to the malarial parasite and the host human cells. Individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient are particularly susceptible to oxidative stress and may experience acute hemolytic anemia (AHA). Before starting a course of primaquine, individuals should be tested for G6PD deficiency to ensure safe administration (1, 2). According to the FDA-approved drug label, individuals with severe G6PD deficiency should not take primaquine (Table 1) (1).

The World Health Organization (WHO) recommends that individuals with G6PD deficiency should be treated with a modified course of primaquine therapy. The recommended course for individuals with G6PD deficiency is a single dose once per week for 8 weeks, while the standard course is daily administration for 14 days (Table 2) (2). The Clinical Pharmacogenetics Implementation Consortium (CPIC) reports that the risk of adverse effects of primaquine therapy for G6PD-deficient individuals is dose-dependent, with the SLD regimen presenting the least risk (Table 3) (3).

Primaquine is contraindicated during pregnancy and is not recommended for breastfeeding individuals when the G6PD status of the baby is unknown (1, 2). Primaquine is not approved for individuals under 6 months of age. Individuals with acute illness that are prone to granulocytopenia or individuals taking another hemolytic medication are also contraindicated from taking primaquine. (1)

Drug: Primaquine

Primaquine is an 8-aminoquinoline antimalarial medication, indicated for the radical cure of P. vivax and P. ovale caused malaria (1, 4). Primaquine is approved by the WHO to prevent relapse of P. vivax and P. ovale malaria, often with chloroquine (in areas with chloroquine-sensitive P. vivax) (2). Though once not recommended in high-transmission settings, the WHO 2022 Malaria Guidelines state that “given the benefits of preventing relapse and in the light of changing epidemiology worldwide and more aggressive targets for malaria control and elimination, the [WHO Global Malaria Programme] group now recommends that primaquine be used in all settings” (2). In severe P. vivax malaria, primaquine therapy should be administered after the completion of other antimalarial therapies that target the active parasites, such as artesunate or chloroquine (2).

The standard administration of primaquine is a daily dose of 0.25 mg base per kg of body weight (mg/kg bw) for 14 days (1, 2). However, some sources recommend a standard adult dose of 15 mg base daily for 14 days, with increased dosing based on either weight over 70 kg or known infection with a frequently relapsing strain of Plasmodium (5, 6). In individuals with G6PD deficiency, either standard dosage presents a significant risk of life-threatening hemolysis, so an adjusted regimen of 0.75 mg/kg bw once a week for 8 weeks with close medical supervision is conditionally recommended by the WHO (2). Primaquine may also be administered as a SLD (0.25 mg/kg bw) in addition to artemisinin combination therapy (ACT) to eliminate malaria caused by P. falciparum in low-transmission areas (2). The benefit of SLD primaquine is primarily targeted to the community level as a means to reduce transmission, as this dose causes sterilization of the mature P. falciparum parasite, rather than curing the infected individual (2, 7, 8).

Primaquine is a pro-drug that needs to be metabolized to exert the desired antimalarial effect. Primaquine is metabolized by 2 different pathways: monoamine oxidase-A (MAO-A) generates the inactive metabolite carboxyprimaquine, while CYP2D6 and CPR generates the 2 active metabolites 5-hydroxyprimaquine and 5-hydroxy-6-desmethylprimaquine (9, 10). Spontaneous oxidation of the active metabolites generates quinoneimine and H₂O₂ that contribute to the antiparasitic activity of primaquine. The enzyme CPR then mediates redox cycling of quinoneimine to the primaquine active metabolites (9, 10). Primaquine has an estimated systemic half-life of 6 hours, necessitating multiple doses for effective radical cure of P. vivax malaria (11).

Primaquine can cause significant oxidative stress due to the accumulation of H₂O₂ in red blood cells, leading to AHA. Under normal homeostatic conditions, NADPH protects cells from oxidative stress. The enzyme G6PD generates NADPH and is particularly critical in red blood cells where it is the only source of NADPH. Individuals who G6PD deficient are especially sensitive to oxidative stress, whether due to endogenous or exogenous sources. As a result, primaquine is contraindicated at standard doses in individuals with G6PD deficiency (1). As discussed below, the residual amount of G6PD activity can vary based on the specific underlying genotype of an individual, so the risk of AHA varies based on the degree of deficiency. The FDA-approved drug label for primaquine advises monitoring blood cell counts and hemoglobin routinely during therapy even in individuals with normal levels of G6PD activity (1).

Contraindications for primaquine treatment include pregnancy, acute illness with a predisposition to granulocytopenia (often seen in rheumatoid arthritis or systemic lupus erythematosus), and medication with other potentially hemolytic drugs (1). The WHO further advise to avoid primaquine therapy in breastfeeding women unless the G6PD status of the breastfed infant is known to be within the normal range (2). One small study found that the estimated primaquine dose that a nursing infant receives following maternal dosing with 0.5 mg/kg/day primaquine was estimated to be 0.6% of the infant daily dose (0.5 mg/day) (12). The amount of primaquine excreted into breastmilk is low, and some sources suggest that G6PD-deficient infants over 28 days of age have a low risk of hemolysis due to primaquine exposure in breastmilk (13); however avoidance of primaquine by nursing mothers when the infants G6PD status is unknown is recommended by WHO, FDA, the US Centers for Disease Control and Prevention, as well as the United Kingdom malaria treatment guidelines (1, 2, 6, 14).

Primaquine is not approved for use in children younger than 6 months of age (2), though one study of infants in Indonesia found that severe clinical outcomes following primaquine treatment in infants under 12 months of age were rare (15). On-going studies suggest that younger children (14 years of age and younger) may require a higher weight-adjusted dose due to lower exposure primaquine and its metabolites (16, 17, 18). The FDA-approved label recommends caution with dose selection for geriatric individuals, as this population has a higher frequency of decreased hepatic, renal, and cardiac function. Initiating therapy at the low end of recommended dosing range is recommended (1). However, both the FDA and the Health Canada approved drug labels clearly state that efficacy and safety of primaquine has not been assessed in individuals over age 65 (1, 5).

In addition to the hemolysis risks, primaquine therapy may also trigger QT prolongation. As such, it should be avoided in conjunction with other medications that prolong the QT interval, in individuals with cardiac conditions such as long QT syndrome, ventricular arrhythmias or bradycardia (1). Other adverse reactions to primaquine can include nausea, vomiting, epigastric distress, abdominal cramps, dizziness, rash, and pruritus. Overdosage of primaquine phosphate can cause these adverse reactions as well as central nervous system and cardiovascular disturbances, cyanosis, granulocytopenia and AHA, among others (1).

Disease: Malaria

Malaria is a serious tropical disease caused by a parasite (Plasmodium) that spreads to humans by infected mosquitos. The only available vaccine is moderately effective and acts only against P. falciparum species (19). Widely recommended antimalarial drugs such as mefloquine or atovaquone-proguanil can be used for prevention –– this is known as chemoprophylaxis. The type of chemoprophylaxis recommended depends upon the individual taking the prophylaxis (namely, age, pregnancy status, and medical comorbidities) and the nature of their exposure –– specifically, the country of residence or traveled to, the length of stay, the species of Plasmodium that are most prevalent, and the level of drug resistance. For individuals residing in malaria-endemic regions, the WHO recommends a variety of preventative chemotherapies that can be used in infants, children, during pregnancy or collectively for the population of endemic areas (2).

Despite chemoprophylaxis, travel to malaria-endemic areas is not without risk. Individuals at elevated risk for malaria complications include pregnant women (20) and adults who have had their spleen removed (21). If travel cannot be avoided, chemoprophylaxis should be combined with additional precautions to avoid mosquito bites, such as bed nets and repellents. In 2021, the WHO estimated 247 million cases of malaria occurred worldwide, and malaria was responsible for 619,000 deaths. (22)

Malaria is found in over 100 countries and occurs throughout most tropical regions in the world. These regions include large parts of Africa, Asia, Central and South America, and parts of the Middle East and Pacific islands (22, 23). Individuals who are heterozygous carriers for sickle cell disease and G6PD deficiency have a protective advantage against malaria, and as a result, the frequency of such genetic conditions is higher in countries where malaria is endemic (24).

Malaria is transmitted to humans by the bite of an infected Anopheles mosquito. Only female mosquitos spread the infection (females feed on human blood, males feed on nectar). Although malaria can also be spread by sharing contaminated needles or via a contaminated blood transfusion, these are rare means of transmission.

There are several different Plasmodium species, but only a few species cause the most malaria cases:

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P. falciparum

• The most common cause of malaria, and death from malaria
• Predominates in sub-Saharan Africa
• Also found in regions of Australasia (Papua New Guinea, Southeast Asia), and the Caribbean (Haiti and the Dominican Republic)

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P. vivax

• A common cause of malaria outside of Africa
• Most frequent species found in Central and South America
• Parasite has a dormant, hypnozoite stage
• Early gametocytes that infect mosquitos

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Plasmodium malariae

• Less common
• Found in most areas where malaria is endemic

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P. ovale

• Less common
• Parasite has a dormant, hypnozoite stage

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Plasmodium knowlesi

• Less common
• Found in some Southeast Asia areas

The first stage of malaria infection begins when an infected mosquito bites the human host. Typically, mosquitos bite at dusk, or during the night. As the mosquito feeds, infective parasite sporozoites (the motile spore-like stage in the life cycle of this parasitic sporozoan, which is the infective agent) are inoculated into humans. The sporozoites travel to the liver, where they invade liver cells and asexually reproduce to form schizonts. The liver schizonts contain daughter merozoites. This process is asymptomatic, and because it occurs outside of the red blood cell (erythrocyte), it is known as the exoerythrocytic stage.

Some species of the parasite (P. vivax and P. ovale) have an additional dormant stage in the liver. The parasite exists as hypnozoites, which can stay in the liver for weeks or months without causing any clinical symptoms.

The second stage of malaria infection is the erythrocytic stage. It begins when the liver schizonts rupture and release the daughter merozoites into the bloodstream. The merozoites invade red blood cells, digest hemoglobin, produce a toxic metabolite (hemozoin), and damage red blood cell membranes. Infected, brittle red blood cells are rapidly broken down (hemolysis) and if too many damaged red blood cells get trapped in the spleen, the spleen can rapidly enlarge (splenic sequestration).

Some of the daughter merozoites differentiate into male or female gametocytes (sexual forms). When they are ingested by a mosquito, they mature, fertilize, reproduce, and develop into sporozoites. When the mosquito feeds again, the sporozoites are inoculated into another human host and the cycle of malaria transmission is complete.

The erythrocytic stage of malaria is usually associated with fever, and malaria should always be suspected in anyone with a fever who has recently returned from a malaria-endemic region, even if antimalarial chemoprophylaxis was correctly followed. Other symptoms and signs include nausea, vomiting, abdominal pain, tachycardia (fast heart rate), diaphoresis (sweating), chills, and myalgia (muscle pain). The complications of malaria infection include severe anemia, cerebral malaria, and multi-organ failure. Without correct diagnosis and prompt treatment, malaria can be fatal.

Gene: G6PD

The G6PD enzyme is encoded by the G6PD gene, which is located on the long arm of X chromosome (Xq28). Variants in the G6PD gene that result in a complete loss of enzymatic activity are not viable; variants observed in living humans generally impact the stability of the enzyme. As such, males can only be hemizygous (have one G6PD allele) while females randomly inactivate one X chromosome during development, resulting in a mosaic expression of either one X chromosome or the other in their somatic cells. This mosaicism can occur in the hematopoietic progenitor cells that give rise to red blood cells, resulting in mixed expression of G6PD alleles. Females with Turner syndrome (45, X) have only one X chromosome and thus are also hemizygous for the G6PD gene. Males with Klinefelter syndrome have an additional X chromosome (47, XXY) and thus 2 G6PD alleles. Thus, it is important to consider the number of X chromosomes for an individual when determining G6PD genotype or phenotype.

Glucose-6-phosphate dehydrogenase deficiency affects 400 million people worldwide, with a worldwide prevalence of approximately 5% (25). Glucose-6-phosphate dehydrogenase deficiency appears to be protective against malaria infection leading to a higher prevalence (more than 25%) in countries where malaria is, or once was, endemic; for example, tropical Africa, tropical and subtropical Asia, the Middle East, and some parts of the Mediterranean (26, 27, 28). In the US, G6PD deficiency is more common among African Americans, affecting approximately 12% (29).

The G6PD enzyme catalyzes the first step in the hexose monophosphate shunt (HMP) pathway, which converts glucose to pentose sugars for nucleic acid synthesis. In this step NADP+ is reduced to NADPH, which protects cells from oxidative stress. In mature red blood cells, the HMP pathway is the only source of NADPH. This promotes the generation of reduced glutathione that protects the sulfhydryl groups of hemoglobin, which are susceptible to oxidation by H₂O₂ and oxygen radicals. Red blood cells that lack G6PD also have a deficiency of NADPH. (30)

Red blood cells that are G6PD deficient have a normal function but are more susceptible to increased oxidative stress (for example, by reactive oxygen species and H₂O₂). Oxidative stress occurs naturally, but is increased during illnesses, such as infections and diabetic ketoacidosis. Oxidative stress can also follow the ingestion of fresh fava beans (favism), and is an adverse effect of several drugs, for example, the antimalarial drugs primaquine and tafenoquine, the antibacterials dapsone and sulfamethoxazole, the skin cancer drug dabrafenib, and the uric acid lowering drugs pegloticase and rasburicase.

While some reports estimate the frequency of G6PD deficiency to be <0.3% in individuals of European, Finish, or Amish descent, other more targeted population analyses have estimated the frequency of G6PD deficiency to be 0.5% in Portuguese males, 6.4% in males from Cyprus, and 8.3% in newborn males in Greece (31, 32, 33, 34). Among Asian populations, estimates broadly range from 2.7–3.5% of individuals will be G6PD deficient (31). However, a study in Cambodia observed 16% of their male study participants were G6PD deficient (<30% activity) while 32% of their female study participants demonstrated an intermediate level of G6PD activity (30–80%) and 4% were deficient (35). Other studies in Asia report the frequency of G6PD deficiency to be approximately 9–31% in Thailand, almost 30% among the Kachin ethnic group from Myanmar and China, 8% in Lao PDR, 9% in Vietnam, and 15.8% in Myanmar (36, 37, 38, 39, 40). Thus, it is difficult to predict the likelihood of an individual being G6PD deficient based solely on their geographic ancestry, as it can vary significantly within commonly used ancestral designations.

Most individuals with G6PD deficiency are asymptomatic –– they have a normal lifespan and may not know they have G6PD deficiency. However, at birth, they may be predisposed to neonatal jaundice, and throughout life, they will be sensitive to oxidizing agents. All individuals with G6PD deficiency should avoid exposure to oxidizing agents when possible, including drugs such as primaquine.

Symptomatic individuals with G6PD deficiency may suffer from episodes of AHA or, the more severe condition, chronic non-spherocytic hemolytic anemia (CNSHA). The management of hemolytic episodes depends on the severity of hemolysis, with more severe cases requiring blood transfusions. Folic acid may be given to prevent the worsening of anemia in individuals with folate deficiency and to induce formation of new red blood cells.

More than 200 genetic variants of the G6PD gene have been identified so far (41), with approximately 400 biochemical and enzyme variants (42). Most known G6PD variants are missense, which can also be inherited as haplotypes that are comprised of more than one variant allele (43). Large deletions are rare, and a complete lack of G6PD activity is thought to be fatal in utero.

The normal (wild-type) copy of the G6PD gene is known as G6PD B, and is found in most Caucasians, Asians, and Africans. Common G6PD variants include:

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G6PD A+ (p.Asn126Asp) has normal enzyme activity and is not associated with hemolysis, and is found in up to 30% of individuals of African descent and approximately 1.5% of Latinos (44, 45)

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G6PD A- (p.Asn126Asp with p.Val68Met) is associated with mild to moderate hemolysis and is found in up to 15% of African Americans (46). Additional A- haplotypes have also been identified, both with the A+ variant with a second variant (p.Asn126Asp with p.Arg227Leu; and p.Asn126Asp with p.Leu323Pro. See Nomenclature table below for additional information) (47)

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G6PD Mediterranean (p.Ser218Phe) can cause severe hemolysis, and is a common pathogenic variant in Caucasians (48)

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G6PD Canton (p.Arg489Leu) can cause severe hemolysis, and is found in Asians (49)

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G6PD Viangchan (p.Val291Met) is the most common G6PD variant among Thais, Laotians, Cambodians, and Malaysians (50, 51)

The WHO recently updated its categorization of G6PD variants into 4 classes based on the median residual enzyme activity in males (expressed as a percentage of normal activity) (52). Class A variants have <20% activity and are associated with CNSHA.

Most individuals with G6PD deficiency have variants that belong to class B (enzyme activity less than 45%). Class B variants are associated with intermittent hemolysis, usually triggered by infection or drugs, but most of the time, affected individuals are asymptomatic. Class C variants show median G6PD activity from 60–150% and are not associated with hemolysis. In class U are all the variants with unknown clinical significance, regardless of activity level. The CPIC has assigned G6PD phenotypes based on G6PD genotypes; the updated WHO categories are provided in Table 4 for completeness (3).

Phenoconversion of G6PD Phenotype

Increased turnover of red blood cells may lead to a temporary increase in G6PD activity as measured by enzyme activity assays. One study of 335 individuals with acute malaria infection (either P. vivax or P. falciparum) found that, on average, G6PD enzyme activity was 10.4% lower in the convalescent, post-infection state than during acute malarial infection. Furthermore, 66–87% of individuals who, following resolution of their malarial infection, had intermediate to severe G6PD deficiency yet they had presented with normal levels of G6PD activity during the acute infection stage (53).

Gene: CYP2D6

The CYP450 superfamily is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are very polymorphic and can result in decreased, absent, or increased enzyme activity. One prominent member, CYP2D6, is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers (54).

Linking G6PD and CYP2D6 Genetic Variation with Treatment Response

Individuals with G6PD deficiency (<20% activity) or intermediate deficiency (20–45% activity) (2) are at a significant risk of hemolysis when treated with the standard primaquine course (daily for 14 days) but have shown tolerance for an extended course with a single dose of primaquine per week for 8 weeks (2). One study in Cambodia found that 95% of the individuals with reduced G6PD activity were able to complete the 8-week course of primaquine and no severe adverse events were recorded (35). A meta-analysis of 20 different trials, based in Africa or Asia, of SLD primaquine found that the proposed WHO regimen (0.25 mg/kg) was, indeed, safe, even in the context of G6PD deficiency (7). While individuals with G6PD deficiency demonstrated a more significant drop in hemoglobin concentration in the 2–3 days immediately following treatment and were more likely to experience hemoglobinuria within 72 hours of primaquine treatment, these effects were transitory and only 2 (out of 194) individuals required further intervention (7). Other risk factors for anemia following SLD primaquine, aside from G6PD deficiency, were high parasite density, young age, and the primary anemia risk factor: low baseline hemoglobin levels (7).

Based on non-clinical metabolism data and limited clinical data, the Health Canada approved drug label for primaquine advises that CYP2D6 polymorphism may be associated with variable clinical response and suggests it may be useful to consider drug-drug interaction or CYP2D6 metabolizer status; it further states that for CYP2D6 PMs, alternative treatment should be considered (5). Several studies in the literature suggest that individuals who are CYP2D6 IM or PMs may not respond well to standard primaquine therapy for the radical cure of P. vivax malaria, which may result in a relapse of malaria symptoms and positive malaria tests weeks to months later (77). There are several case reports that link CYP2D6 reduced enzymatic activity or IM/PM genotypes with malaria relapse after primaquine therapy (78, 79, 80, 81, 82, 83). A study of 25 individuals found that IM or PM phenotypes were associated with malaria relapse, while individuals with CYP2D6 NM phenotype did not experience relapse following treatment with chloroquine and primaquine (84). Additionally, a case-control study of 57 individuals found that CYP2D6 IM or PM phenotype (determined either by genotype or inferred based on reduced dextromethorphan metabolism) strongly correlated with increased frequency of malaria relapse (85). A prospective cohort study with 190 individuals found P. vivax malaria relapse was more common among individuals with reduced CYP2D6 activity alleles (86). A study of 260 individuals living in a P. vivax endemic region of the Amazon found a significant correlation between CYP2D6 reduced-function genotype (AS<1) and risk of malaria recurrence (87). In Korea, individuals with CYP2D6 IM phenotype were more likely (an odds ratio of 2.33) to have P. vivax malaria relapse even after treatment with primaquine (82). Similar results were observed in a study with 120 individuals in the Yunnan Province of China, where the c.886C>T and CYP2D6*2 variants were associated with relapse of P. vivax malaria after treatment with chloroquine and an 8-day course of primaquine (88). A meta-analysis of 9 studies that included a total of 970 individuals from Asia, Brazil, and Oceania found that CYP2D6 IM and PMs were nearly twice as likely to experience malaria relapse following primaquine therapy as compared to NM or UM individuals (82). In contrast, a small study of 51 individuals treated with chloroquine and primaquine combination therapy did not observe any significant enrichment for CYP2D6 IM or PMs among the relapse group, though the limited number of relapses and sample size may have left this study underpowered (89). A larger study with 157 subjects from Australia also found no association between CYP2D6 activity and malaria relapse (90).

Reduced CYP2D6 activity was found to be associated with reduced clearance of P. falciparum gametocytes in SLD primaquine therapy in a study of 774 individuals from Africa; however, even with reduced CYP2D6 activity, the addition of SLD primaquine was more effective to clear gametocytes than ACT alone (91). This same study found no significant impact of CYP2D6 activity on the frequency or degree of anemia following SLD primaquine in G6PD deficient individuals (91). Similarly, a study of 157 children, aged 1–10 years, found no difference in the incidence or severity of acute hemolysis nor in efficacy against the Plasmodium parasites among individuals with reduced CYP2D6 or G6PD activity treated with ACT with SLD primaquine, leading the authors to conclude that this treatment regimen is both safe and sufficient to reduce P. falciparum transmission (7). The WHO guidelines do not require G6PD testing when administering SLD primaquine (2).

The G6PD and CYP2D6 Gene Interactions with Medications Used for Additional Indications

Medications that can induce oxidative stress in red blood cells can trigger hemolysis readily in individuals with G6PD enzyme deficiency. Many of these medications are antimalarials (tafenoquine, for example) but many more medications pose a hazard for G6PD deficient individuals.

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Urate-lowering medications: both refractory gout and tumor lysis syndrome can cause systemic elevation of urate levels, medications such as rasburicase and pegloticase are uricase enzymes that aid in the breakdown of uric acid into more soluble metabolites. These reactions produce H₂O₂ as a byproduct, thus increasing oxidative stress in the body.

●

Kinase inhibitors: anticancer medications such as dabrafenib may also increase oxidative stress.

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Antimicrobial medications: nitrofurantoin, often used for urinary tract infections, was determined to be a medication of moderate risk for AHA in G6PD-deficient individuals by CPIC and may call for additional monitoring. In contrast, CPIC found sulfamethoxazole to be a medication with low-to-no risk in G6PD deficient individuals. (3)

Additional information on gene-drug interactions for G6PD are available from PharmGKB, CPIC and the FDA (search for “G6PD”).

The CYP family of enzymes is involved in the metabolism of many substances and CYP2D6 especially has been implicated in altered pharmacologic responses for many compounds. The drugs can be categorized into many different classes:

●

Antipsychotics—for example, aripiprazole, risperidone, thioridazine and—to a lesser extent—clozapine is metabolized by CYP2D6. According to the FDA, aripiprazole dosage should be reduced for PMs and thioridazine is contraindicated for individuals who are known to have reduced CYP2D6 activity due to increased risk of potentially fatal side effects. The UMs may have a decreased plasma concentration of risperidone.

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Tricyclic antidepressants—for example, amitriptyline, and imipramine may require dosage adjustments, potentially guided by therapeutic drug monitoring, to achieve the desired therapeutic range in UMs or PMs. Ultimately, tricyclic antidepressants may be ineffective in CYP2D6 UMs.

●

Serotonin and norepinephrine reuptake inhibitors—for example atomoxetine and venlafaxine may have reduced efficacy in UMs at standard doses while PMs are at risk of elevated plasma concentrations for both medications. The Dutch Pharmacogenetics Working Group advises against the use of venlafaxine in CYP2D6 PMs and IMs.

●

Cardiovascular dysfunction—for example, carvedilol, metoprolol, and propafenone are all metabolized by CYP2D6, and PMs will have higher plasma concentrations of these medications compared with NMs resulting in potentially undesired side effects or (in the case of metoprolol) extensive slowing of the heart rate.

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Anticancer medications—for example, tamoxifen is activated by CYP2D6, and IMs or PMs may have reduced benefit from tamoxifen therapy.

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Pain management—for example, codeine and tramadol are pro-drugs that require activation by CYP2D6 to achieve the desired analgesic effect.

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Various therapies for genetic disorders—for example eliglustat used in the treatment of Gaucher disease, and deutetrabenazine used in the treatment of Huntington disease—have reduced dose recommendations for CYP2D6 PMs. The CYP2D6 UMs may not achieve adequate concentrations of eliglustat and therefore CYP2D6 genotyping is required before initiation of eliglustat therapy.

It is important to note that CYP2D6 is the most common biomarker in drug responses for FDA drug labels, the list provided here is by no means exhaustive. Additional information on gene-drug interactions for CYP2D6 are available from PharmGKB, CPIC and the FDA (search for “CYP2D6”).

Genetic Testing

The NIH Genetic Testing Registry (GTR) displays genetic tests that are available for primaquine response, the G6PD gene, and the CYP2D6 gene. Molecular genetic testing can be used to confirm the diagnosis of G6PD deficiency, and testing may also be used to screen females with a family history of G6PD deficiency to see if they are carriers.

While many biochemical G6PD variants are known, the genetic underpinnings of some of these variants may still be unknown. Additionally, quantitative, or semi-quantitative tests for G6PD enzyme activity may be more readily available in some settings. Whether the clinical test is biochemical or molecular, assessment of G6PD enzyme activity is required before administering primaquine for the radical cure of P. vivax or P. ovale malaria, per the FDA (1). A number of point-of-care tests have been developed and tested (92, 93, 94) to improve the accessibility of G6PD genetic testing before administration of medications like primaquine, though the availability of such testing in areas with the highest malarial burden is still lacking (95).

The available CYP2D6 tests include targeted single-gene tests as well as multi-gene panels or genome-wide sequencing tests. In addition, variant CYP2D6 alleles to be included in clinical genotyping assays have been recommended by the Association for Molecular Pathology (96). The test results may include an interpretation of the individual’s predicted metabolizer phenotype, which can be confirmed by checking the diplotype and calculating the CYP2D6 activity score, as described in the “CYP2D6 Alleles” section above. When individuals have more than 2 copies of the CYP2D6, the copies of the allele are denoted by an “xN”, for example, CYP2D6*1/*2x2. Some laboratories also use the notation of DUP to indicate an increase in copy number, but the report does not always specify the number of duplications nor the allele that has been duplicated due to technical limitations.

Therapeutic Recommendations based on Genotype

This section contains excerpted ¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature for Selected G6PD and CYP2D6 Alleles

Acknowledgments

The author would like to thank Amit Sharma, PhD, Former Director of the National Institute for Malaria Research, Group Leader, Molecular Medicine Group, ICGEB, New Delhi, India, and Katherine Riden, PharmD, AccessDx Laboratory, Houston, TX, USA for reviewing this summary.

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