A Study of the Pharmacokinetics of Primaquine in Lactating Women and Breastfed Infants for the Radical Treatment of Uncomplicated Maternal P. Vivax

Background The weight of malaria falls most heavily on young children and pregnant women but studies of the safety of antimalarials in pregnancy and lactation are few. The only recommended medication used for radical treatment of P.vivax is primaquine. The 2010 WHO malaria guidelines recommend its use in all patients with P.vivax infection in areas of low transmission, in the absence of contraindications. Primaquine is contraindicated in pregnancy. The postpartum period presents a key opportunity to definitively treat women who suffer multiple malaria relapses during pregnancy. The 2010 WHO malaria treatment guidelines allow for primaquine use during lactation but there are no studies to date quantifying primaquine excretion in breast milk and the dose that breastfed infants would be exposed to is unknown. The investigators propose to study the pharmacokinetics of primaquine in maternal and infant plasma and in breast milk during a 14 day radical treatment of P.vivax.

Rationale

The global burden of malaria is great, with approximately 1-2 million deaths each year and many times that number of productive days lost to illness. Plasmodium vivax is the most prevalent malarial species, resulting in 132-391 million clinical infections each year and 80-90% of malaria in Asia, the Middle East, and the Western Pacific. Despite its prevalence, P.vivax has not been a focus of research until recently, and its effects and optimal treatments are still not fully understood. Though infrequently a fatal infection, P.vivax causes high levels of morbidity due to the chronic nature of the infection. Because of dormant liver stages (hypnozoites), illness can continue to recur for years, even after effective treatment has eliminated the parasites from the blood. In settings where there are hopes for malarial eradication, this means infected persons continue to be hosts even if vector-borne transmission is temporarily interrupted, and could potentially start a new cycle of transmission with each relapse. Each of these relapses causes a significant amount of morbidity and a small mortality risk for those infected.

These burdens are magnified during pregnancy when women experience relative immune suppression and can experience relapses every 4-8 weeks. P.vivax malaria in pregnancy is associated with low birth weight and anaemia; thrombocytopaenia; increased risk of fetal loss, premature delivery, neonatal and infant mortality; and, in some areas, risk for congenital malaria (a severe, sepsis-like illness). In Southeast Asia, where the investigators propose to conduct our study, the majority of cases of congenital malaria are from vivax infection. These women may have some respite during the postpartum period, with relapses spaced further apart, but frequently relapse again in subsequent pregnancies. New pregnancies during the end of lactation are common in many malaria endemic areas, including our setting, making definitive treatment of vivax infections in these women very challenging in the absence of data about the safety of primaquine for the breastfeeding infant.

Though the anti-malarial pharmacopeia has expanded over the past decade, primaquine remains the only definitive treatment for the hypnozoite forms of Plasmodium vivax and ovale. First synthesized in 1946, a 14 day treatment eradicates the parasites from the liver. However, this medication has been associated with a risk for methemoglobinemia, and acute intravascular haemolysis in glucose-6-phosphate-dehydrogenase (G6PD) deficient hosts (common in malaria-endemic areas). The elevations in methemoglobin are generally modest and asymptomatic, but occasionally significant methemoglobinemia can cause cyanosis and shortness of breath requiring discontinuation of the medication. Primaquine is not considered safe in pregnancy because of the possible risk of haemolysis and methaemoglobin in the fetus. The most recent WHO malaria guidelines (2010) have conflicting information about the its use during lactation. They cite breastfeeding as a contraindication for primaquine administration for P. falciparum malaria, but permit the use of primaquine for P. vivax during lactation if the breast fed infant is not G6PD deficient. No studies have ever been done in lactating women to determine the safety of primaquine in breastfeeding or the optimal time of administration, however, the relaxation of guidelines in infancy suggest potential for its safe use in lactation. Some authors note that primaquine's once daily dosing might allow for safe breastfeeding if the mother pumps the milk at the time when peak milk concentrations are expected and discards that milk.