Tafenoquine and Primaquine in Colostrum and Breast Milk

• Status: Not yet recruiting
• Trial end date: 2023-10-31
• Target enrollment: 0
• Participant gender: Female

Summary

Each year almost a million infants are born small for gestational age due to malaria infection in pregnancy. These infants are at risk for stillbirth or neonatal death, and being born too small predisposes the survivors to increased metabolic diseases later in life. Plasmodium vivax (PV) is the second most common malaria species globally. Its relapsing nature results in multiple episodes of PV in a single pregnancy, compounding growth restriction and stillbirth risk. Women with PV in one pregnancy may harbor dormant parasites (hypnozoites) in their liver the cause illness and poor fetal growth in a subsequent pregnancy.

Only radical cure with 8-aminoquinolines (8AQ)- primaquine (PMQ) or tafenoquine (TQ) - can eliminate hypnozoites, but these drugs are contraindicated in pregnancy. The postpartum period presents a key window of opportunity for giving radical cure to women of childbearing age with PV. Pharmacokinetic data is needed to support safe use of these drugs postpartum and World Health Organization has identified pharmacokinetic studies of 8AQ in lactation as a research priority.

Primaquine is excreted minimally in mature breast milk, at <1% of the weight-adjusted relative infant dose (RID). As the main adverse event associated with both 8AQ - hemolysis glucose-6-phosphate dehydrogenase (G6PD) deficient individuals - is dose-dependent and negligible at low doses, this finding strongly supports its safe use in later lactation. This study is needed to determine if primaquine can also be given safely in the early postpartum period. There is no published data on tafenoquine excretion in breastmilk, and this study would quantify safety throughout early and late lactation.

Drug safety studies in lactation are essential to ensure medications are not denied and unnecessary interruption of breastfeeding is avoided. Demonstration of safety of radical cure for breastfeeding women in the postpartum period would allow women with PV in pregnancy and lactation to receive 8AQ after delivery, preventing illnesses in the postpartum period and subsequent pregnancies. Improved uptake of radical cure through elimination of unnecessary contraindications supports malaria elimination and community health.

The main purpose of this study is to characterize the transfer of tafenoquine and primaquine in breast milk of mothers receiving radical cure doses of 8AQ throughout the different phases of lactation - colostrum, transitional milk, and mature milk - in order to determine the degree of infant exposure.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Oxford
• Collaborator: Mahidol Oxford Tropical Medicine Research Unit
• Treatments: Primaquine; Tafenoquine

Criteria

Inclusion Criteria:

• Mother

• Lactating women >= 16 years old who are breast feeding one child who fits the time window for the respective study arm

• Planning to breastfeed for the duration of the study

• Willingness and ability to comply with the study protocol for the duration of the study

• Willingness to delay pregnancy until the end of the period of drug exposure (14 days for PMQ and 90 days for TQ)

• Current pregnancy excluded by urine pregnancy test and ultrasound OR immediate postpartum status (≤2 months)

• Can understand information about the study and provide consent

• Children

• Healthy children falling into the time window for the respective study arm

• ≤ 5 days for Arms 1 & 3

• > 14 days for Arm 2

Exclusion Criteria:

• Mothers

• Known hypersensitivity to PMQ or TQ, defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis

• Known Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in mother defined as G6PD activity <70% of normal male population median by spectrophotometry

• Presence of any condition which in the judgement of the investigator would place the participant at undue risk or interfere with the results of the study

• Alkaline phosphatase (ALT) > 2x the upper limit of normal (ULN)

• Pregnancy

• Screening hematocrit (Hct) <33%

• Known history of severe jaundice in a previous child

• Known history of psychiatric illness or abnormal depression screening score

• Blood transfusion within the 3 months before screening

• Children

• Known hypersensitivity to primaquine or tafenoquine, defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis

• Known Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in child defined as G6PD activity <70% of normal male population median by spectrophotometry in children

• Presence of any condition which in the judgement of the investigator would place the participant at undue risk or interfere with the results of the study

• Screening Hct <33%

• Estimated gestational age at birth < 38 weeks

• Blood transfusion within the 3 months before screening

• Evidence of birth asphyxia (5 min Apgar score <7)

• Moderate or severe jaundice as defined as total serum bilirubin above treatment line on day 1 (before maternal dose)