What is the action of primaquine?

8.1.1 Primaquine and its Metabolites

Primaquine is rapidly excreted, with an elimination half-life of about 4 h (Carson et al., 1981; Greaves et al., 1980), and metabolises into a complex array of a dozen or so distinct moieties. One metabolite is carboxy-primaquine, which has been detected in plasma within 30 min of dosing, reaching plasma concentrations 10-fold higher than primaquine (Mihaly et al., 1985). Carboxy-primaquine, however, appears physiologically inert, both with respect to toxicity and therapeutic activity. On the other hand, some moieties are highly unstable and oxidatively volatile. For instance, 5-hydroxy-6-methoxy-8-aminoquinoline (5H6MQ) was 2500 times more potent than primaquine in stimulating the PPP in normal RBCs (Baird et al., 1986b). It is likely to be one or several metabolic products of primaquine which is the active agent against the parasites, rather than the parent compound itself (Beutler, 1969; Carson et al., 1981; Fletcher et al., 1988).

The molecular events triggering haemolysis remain unproven, though several mechanisms of action have been proposed, including the build-up of methaemoglobin (metHb) causing damage to the cell membrane, and oxidative damage provoked by primaquine metabolites. The relative significance of these pathways remains unclear. In vitro haemotoxicity assays have demonstrated that it is cytochrome P450-linked pathways which metabolise the breakdown of primaquine by redox reactions into its haemotoxic metabolites, including the formation of metHb and the generation of reactive oxygen intermediates (Ganesan et al., 2009), in a dose-dependent response (Ganesan et al., 2012); the assay found no haemotoxic effect of primaquine when exposed to cells in the absence of these cytochromes. Further study with isoenzyme activity screening and steady state kinetic data has identified two cytochrome P450 enzymes (MAO-A and 2D6) to be strongly involved in primaquine metabolism, and reported that the metabolites generated by these enzymes made it likely that the drug’s toxicity and efficacy were enabled by the same single-cytochrome pathway, making it unlikely that these two properties of the drug could be separated (Pybus et al., 2012). Further study is required to support these findings and determine the relative influence of inhibitors and inducers of these specific cytochrome enzymes to test their individual effect on the drug’s efficacy and toxicity. Similarly, while a number of primaquine metabolites have been identified, none have been definitively associated with activity against the Plasmodium parasite (Baird and Hoffman, 2004; Myint et al., 2011).

3.2 Primaquine

Primaquine is used in patients with Plasmodium ovale and Plasmodium vivax infections to clear the latent hepatic hypnozoite stage of the parasite and prevent relapse and transmissibility. It is primarily metabolized by CYP1A2 and CYP3A4.155 Although ethnicity has been found to be significantly associated with plasma levels of primaquine, the genetic polymorphisms underpinning this variability, or their impact on efficacy or toxicity are yet to be characterized.39,156,157

The first records of variability in response to antimalarials dates back to World War II when African–American soldiers were found to experience higher rates of acute hemolysis when they received primaquine compared to their Caucasian counterparts.158 The basis of these observed differences was later attributed to glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder,159 common in sub-Saharan Africans (∼10–25%).160 The G6PD locus is highly polymorphic, so in clinical practice, prospective qualitative and quantitative tests are performed in patients requiring primaquine.161

4.5 Detection of G6PD deficiency

Primaquine is an essential tool for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of P. vivax. It is also the only antimalarial agent against the sexual stages of P. falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission (Baird et al., 2011; Bousema et al., 2011). However, the difficulties of identifying glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine’s widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants (Howes et al., 2013b).

G6PD is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria-endemic countries (Cappellini et al., 2008; Howes et al., 2012). The spatial extent of P. vivax malaria overlaps widely with that of G6PD deficiency; unfortunately, the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. According to the past and current data on this unique pharmacogenetic association, G6PDd is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden (Wells et al., 2010). G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand G6PD deficiency and primaquine-induced haemolysis in depth to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination (Howes et al., 2013a).

Primaquine

Primaquine, an 8-aminoquinoline active against hypnozoites of P. vivax and P. ovale in the liver, is the only agent with the potential for yielding complete resolution of malaria caused by these organisms.1,2,8,9 Primaquine combined with clindamycin is also effective in the treatment of P. jirovecii pneumonia. Recently, primaquine in a dose of 30 mg base/day (52.6 mg salt/day) showed efficacy as prophylaxis against P. falciparum (88% protection) and P. vivax (92% protection) malaria.60 Primaquine acts by interfering with plasmodial mitochondrial function, possibly through its effects on the electron transport chain and pyrimidine biosynthesis. Primaquine phosphate, which is available only in oral form, is rapidly absorbed (bioavailability 96%), widely distributed and hepatically converted to three metabolites. It is unclear whether the parent compound or the metabolites possess the antimalarial activity.

Primaquine phosphate is formulated in tablets containing 26.3 mg of the salt, equivalent to 15 mg of the base. Dosages are given in Table 157-1. Relapse of P. vivax after conventional primaquine treatment has been described in up to 30% of cases in Papua New Guinea, the Solomon Islands, Thailand and other parts of South East Asia.61 Therefore, for cases acquired in South East Asia or Oceania, the dose should be increased to 22.5 mg base per day.

The principal toxicity of primaquine is hemolysis in patients who are G6PD-deficient, and thus G6PD levels should be measured before therapy is begun. Alternative dosing regimens of primaquine are required in G6PD-deficient patients. Headache, nausea, vomiting and abdominal cramps have been reported. At higher doses, mild anemia, cyanosis (due to methemoglobinemia) and leukopenia may occur. Rarely, neurotoxicity, arrhythmias, hypertension and agranulocytosis occur.

How does primaquine work in the body?

How does Pamaquine work?

Why primaquine is used in malaria?

What is in primaquine?