Pharmacokinetics of Primaquine and Tafenoquine in Lactating Women - Towards Equitable Radical Cure of Vivax Malaria
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Pharmacokinetic: Distribution half -life
研究概览
简要总结
In Papua New Guinea, administration of primaquine (PQ) or tafenoquine (TQ) to breastfeeding mothers is contraindicated during the first six months postpartum, when infants are recommended to be exclusively breastfed, because of a lack of comprehensive pharmacokinetic data on PQ/TQ neonatal and infant exposure via breast milk. The therapeutic restriction of PQ/TQ use in lactating women during the first six months postpartum effectively translates into ~10% of females being excluded from radical cure in endemic areas at any time. This is because many at risk women live in remote areas, are frequently lost to follow-up, or may have conceived again before they reattend. As a result, radical cure is rarely achieved and women are exposed to recurrent infections and cumulative risk of anaemia. Relapses may occur for years, placing subsequent pregnancies at risk and perpetuating intergenerational failure of fetal growth. They also contribute to malaria transmission, thus household and community exposure to vivax malaria.
The goal of the present study is to determine how much PQ/TQ is transferred to a suckling baby, if a mother receives a treatment course of PQ/TQ at time of delivery. We also want to confirm that this treatment is safe and has no major side effects for babies in Papua New Guinea.
The study Interventions areas follows: Group 1 - Participants receive PNG standard of care; PQ given 6-months postpartum; Group 2 - Participants receive a 14-day treatment regimen of PQ, at the standard dose prescribed in PNG for vivax radical cure (0.5 mg/kg/day for 14 days); Group 3 - Participants receive an accelerated high-dose 7-day treatment regimen of PQ, as per current WHO recommendations (1.0 mg/kg/day for 7 days); Group 4 - Participants receive a single dose of 300mg tafenoquine.
All participants will be monitored for a total duration of 6 months, with the safety, tolerability, pharmacokinetics and preliminary relapse efficacy of PQ/TQ evaluated at standardised time points over this period (Day 0, 1, 3, 6, 8, 15, 20, 28, and Month 2, 3, 4, 5 and 6). At each of these time points, participants will be asked to describe any symptoms they may be experiencing, participate in a medical examination, and provide a blood and breast milk sample for drug analysis and safety (biochemistry and haematology testing). The investigators will also collect a small blood sample (heel prick) from the infant to measure drug concentrations and safety testing.
详细描述
Global malaria eradication requires universal and equitable access to effective antimalarial treatment. More than 2.5 billion people are at risk of infection with Plasmodium vivax. Unlike falciparum malaria, P. vivax forms dormant liver-stage parasites (hypnozoites) that can reactivate (relapse) causing recurrent febrile illness after the initial infection. Women are at increased risk of vivax malaria during pregnancy and postpartum, when they are at higher risk of P. vivax infections than P. falciparum malaria. Over 80% of these infections are relapses, rather than new infections but pregnant and lactating women cannot be treated with the available anti-relapse drugs. This is because the 8-aminoquinolones, primaquine (PQ) and tafenoquine (TQ), can cause potentially life-threatening haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient babies, and there is concern that the drugs are transferred in breast milk. If anti-relapse treatment could be given immediately on delivery and before discharge, it would dramatically reduce the risk of vivax relapses which currently affect ~10% of women in countries like Papua New Guinea (PNG).
This study aims to accelerate maternal access to PQ/TQ by confirming minimal transfer of PQ or TQ not only in mature breast milk (>2 weeks postpartum; current data available from a pharmacokinetic (PK) study in Thailand), but also in colostrum and transitional breast milk in the first two weeks after birth. Generating PK data for TQ is also critical. Maternal treatment could then be initiated before hospital discharge to prevent postpartum relapses and maximise benefit for health outcomes and malaria control.
This open-label study has the following objectives and hypothesis:
Primary Objective: To determine the transfer of primaquine (and primary metabolite carboxyprimaquine) and tafenoquine in breast milk (colostrum and transitional milk) and determine associated relative infant exposure.
Secondary objectives include; i) To compare haematological and hepatorenal indices in exposed and unexposed mother-infant pairs as a measure of safety, and ii) to assess maternal tolerability of early postpartum primaquine (PQ) and tafenoquine (TQ) treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •≥18 years of age
- •Both mother and infant have G6PD activity >70% (normal activity; SD Biosensor)
- •They have no significant co-morbidity
- •Delivered a live singleton baby within past 48-hours
- •Rapid diagnostic test negative for malaria
- •No history of hypersensitivity to 8-aminoquinoline drugs
- •Plan to exclusively breastfeed for at least two months
- •History of vivax malaria (as per health book)
- •They can attend follow-up assessments for the duration of the study
排除标准
- •Either mother/infant have G6PD activity <70% (SD Biosensor)
- •Either mother/infant have significant co-morbidity
- •Mother did not deliver a live singleton within past 48-hours
- •Mother/infant are rapid diagnostic test positive for malaria
- •Mother has a history of hypersensitivity to 8-aminoquinoline drugs
- •Mother does not plan to exclusively breastfeed for at least two months
- •Mother does not have a history of vivax malaria (as per health book)
- •Cannot or are not willing to attend follow-up assessments for the duration of the study
研究组 & 干预措施
Group 2 - PQ14
Daily oral primaquine as 0.5 mg/kg per day for 14 days, taken with food and water
干预措施: Daily primaquine (0.5 mg/kg per day) for 14 days given with food food and water (Drug)
Group 3 - PQ7
Daily oral primaquine 1 mg/kg per day for 7 days, taken with food and water
干预措施: Daily primaquine 1 mg/kg per day for 7 days given with food and water (Drug)
Group 4 - TQ
Single dose tafenoquine as 300mg taken with food and water
干预措施: Single-dose tafenoquine given with food and water to prevent gastrointestinal discomfort (Drug)
Group1 - control
Participants will receive no intervention at time of delivery. As per standard care in PNG, each participant will receive primaquine at 6-months postpartum (completion of study procedures).
结局指标
主要结局
Pharmacokinetic: Distribution half -life
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ)
Pharmacokinetic parameters of primaquine (PQ) (and primary metabolite carboxyprimaquine) and tafenoquine (TQ) in breast milk (colostrom and transitional milk) to determine relative infant exposure. Based on drug concentrations determined from venous blood samples (mothers) and heel prick samples (infants) collected at baseline (Day 0) 1, 3, 6, 8,15, 20 and 28 (and 56 for Group 4).
Pharmacokinetic: Termination elimination half-life
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
Pharmacokinetic: Absorption half-life
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
Pharmacokinetics: Clearance
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
Pharmacokinetics: Volume of distribution
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
Pharmacokinetics: Maximal concentration
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
Pharmacokinetics: Area under concentration-time curve
时间窗: Group 2 and 3: 28 days after first drug dose (PQ) and Group 4: 56 days after drug administration (TQ).
次要结局
- Safety: Change in haemoglobin over 28 days(Up to 28 days)
- Safety: Change in haemotocrit over 28 days(Up to 28 days)
- Safety: Change in methaemoglobin over 28 days(Up to 28 days)
- Safety: Change in maternal and infant weight in kilograms over 28 days(Up to 28 days)
- Safety: Frequency of self-reported adverse events(Up to 7 days after completion of treatment regimen)
- Safety: Breastfeeding behaviour(Up to 14 days)
- Change in alanine transaminase (ALT) over 28 days(Up to 28 days)
- Change in total bilirubin (TBil) over 28 days(Up to 28 days)
- Change in creatinine (Cr) over 28 days(Up to 28 days)
研究者
Brioni Moore
Associate Professor
Curtin University