Primaquine Pharmacokinetics in Lactating Women and Their Infants
Information source: University of Oxford
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Vivax Malaria
Intervention: Primaquine (Drug)
Phase: Phase 1
Status: Recruiting
Sponsored by: University of Oxford Official(s) and/or principal investigator(s): Rose McGready, MD, Principal Investigator, Affiliation: University of Oxford
Overall contact: Rose McGready, MD, Phone: +66 (0) 55-545-021, Email: rose@shoklo-unit.com
Summary
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.
Some inferences about the expected behavior of primaquine in lactation can be drawn from its
known pharmacologic properties. Primaquine pharmacokinetics have been well characterized in
healthy subjects and malaria patients after single and multiple oral dosing. Peak
concentrations are reached within 2-3 hours after dosing and the plasma elimination
half-life is ~7 hours. It is extensively distributed in the tissue and largely metabolized
to inert carboxyprimaquine, the major plasma metabolite, which undergoes further
biotransformation to unknown metabolites that are probably more toxic than the parent
compound. The identification of other metabolites in humans has been difficult to pursue
because the expected aminophenol metabolites are unstable.
No pharmacokinetic studies have been done to measure primaquine excretion in breast milk. A
few studies have been done of other antimalarials during lactation and have shown low levels
of drug in breast milk during treatment.
Clinical Details
Official title: A Study of the Pharmacokinetics of Primaquine in Lactating Women and Breastfed Infants for the Radical Treatment of Uncomplicated Maternal P. Vivax
Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Pharmacokinetic Parameters of Primaquine and Carboxyprimaquine in breast milk. Area Under Curve (AUC)
Secondary outcome: Pharmacokinetics Parameters of Primaquine and Carboxyprimaquine in blood. Area Under Curve (AUC).Concentration of Primaquine in saliva and urine. Area Under Curve (AUC). Primaquine dosage in infant - the relative infant dose. Area Under Curve (AUC). Assessment of adverse events during primaquine administration Hematocrit levels in mother and child
Detailed description:
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.
Some inferences about the expected behavior of primaquine in lactation can be drawn from its
known pharmacologic properties. Primaquine pharmacokinetics have been well characterized in
healthy subjects and malaria patients after single and multiple oral dosing. Peak
concentrations are reached within 2-3 hours after dosing and the plasma elimination
half-life is ~7 hours. It is extensively distributed in the tissue and largely metabolized
to inert carboxyprimaquine, the major plasma metabolite, which undergoes further
biotransformation to unknown metabolites that are probably more toxic than the parent
compound. The identification of other metabolites in humans has been difficult to pursue
because the expected aminophenol metabolites are unstable. Until recently, techniques to
separate positive and negative enantiomers for primaquine and carboxyprimaquine have not
been possible, again obscuring the toxic and therapeutic mechanisms of the drug.
Primaquine has limited oral bioavailability and adult plasma concentrations are generally
low, making dangerously high concentrations in maternal milk unlikely from a theoretical
standpoint. However, recent data suggests that a previously unrecognized sex difference
exists in the pharmacokinetics of the medication in men and women, with women accumulating
higher drug concentrations than men. Since side effects of primaquine appear to be
dose-related, this finding could be significant. The time to maximum concentration is about
2-3 hrs (longer for women than for men) and the investigators would expect to see a short
lag in reaching peak breast milk concentrations. Primaquine has a low molecular weight
(259) and slightly basic pH making it more likely to transfer into the breast milk.
Literature on medication pharmacokinetics in breast milk is sparse but has begun to capture
the interest of researchers and human rights activists who note that women are often
systematically excluded from medical research by virtue of pregnant or lactating status. As
a result, during these two states the pharmacokinetic properties of drugs remain poorly
understood, and much of our clinical therapeutic approaches are based on consensus and
conjecture. No pharmacokinetic studies have been done to measure primaquine excretion in
breast milk. A few studies have been done of other antimalarials during lactation and have
shown low levels of drug in breast milk during treatment. The frequent venous sampling
necessary for pharmacokinetic research is not ideal for participants, especially in
pediatric populations. Recent efforts have been made to evaluate the usefulness of
capillary or saliva samples as alternative sampling measures.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Lactating women aged 18 years and older who are breast feeding one infant aged more
than 28 days.
- G6PD normal
- History of proven P. vivax malaria that has not been treated with primaquine
- Willingness and ability to comply with the study protocol for the duration of the
trial
- Written informed consent provided
Exclusion Criteria:
- Known hypersensitivity to primaquine, defined as history of erythroderma/other severe
cutaneous reaction, angioedema or anaphylaxis
- Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in mother
- Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in infant
- Pregnancy (urine test for HCG to be performed on any woman of child bearing age
unless menstruating)
- Blood smear positive for malaria at the time of enrolment
- Presence of intercurrent illness or any condition which in the judgement of the
investigator would place the patient at undue risk or interfere with the results of
the study
- Hematocrit (HCT) <25% in the mother or <33% in the infant
- Use of medications other than antipyretics in the past 7 days or Chloroquine in the
past 2 months.
- Use of primaquine since most recent malaria episode.
Locations and Contacts
Rose McGready, MD, Phone: +66 (0) 55-545-021, Email: rose@shoklo-unit.com
Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Recruiting Rose McGready, MD, Phone: +66 (0) 55-545-021, Email: rose@shoklo-unit.com Mary E Gilder, MD, Phone: +66 (0) 55-545-021, Email: melliegilderjr@gmail.com Mary E Gilder, MD, Principal Investigator
Additional Information
Starting date: November 2012
Last updated: August 27, 2013
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