Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics of Lumefantrine and Population Pharmacokinetics of Lumefantrine Among Ugandan Children
试验速览
- 阶段
- 4 期
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Pharmacokinetic (PK) exposure parameters of lumefantrine
研究概览
简要总结
Despite preventive programs, effective case management is still the cornerstone in malaria control.
This study is as a strategy towards improved recommendations in resource limited countries during artemether -lumefantrine (AL) treatment in order to maximize the public health benefits.
This is observational population pharmacokinetics study with a nested comparative bioavailability study.The study is intended to describe the variability in lumefantrine blood levels among under five year old Ugandan children with uncomplicated falciparum malaria receiving current standard artemether-lumefantrine dose regimens. Findings will form a basis for development of rational dosage recommendations. The nested comparative bioavailability study will explore effect of profiled local food intake (maize porridge plus vegetable oil versus milk) on lumefantrine uptake. As a strategy towards improved recommendations in resource limited countries during AL treatment in order to maximize the public health benefits. As a secondary objective we will correlate the variability in lumefantrine uptake to malaria treatment outcome and safety profile in this population.
Research hypotheses
- The population pharmacokinetic profile of lumefantrine among under five year old children in Uganda with uncomplicated falciparum malaria is not affected by demographic factors.
- There is no difference in the bioavailability of lumefantrine when artemether-lumefantrine is received with maize porridge plus vegetable oil versus milk among under five year old Ugandan children treated for uncomplicated falciparum malaria.
详细描述
This is an observational study with a nested comparative bioavailability study among children based at Mulago Hospital, Kampala Uganda. It is a part of profiled doctoral study project aimed at improving artemether-lumefantrine drug use among children in resource limited settings in order to maximize public health benefits. It involves initial healthy volunteer studies, quantitative analytical studies and finally this pediatric patient study.
Artemether-lumefantrine is currently the first line treatment of uncomplicated malaria in Uganda and several countries in sub Saharan Africa. Currently the recommended dose regimens for children, the most vulnerable population are still empirically weight based derivations based on mainly clinical experience from studies done among adults. Yet children are physiologically different from adults. In particular lumefantrine, a long acting agent ensuring radical cure is highly lipophilic, and has variable oral bioavailability. High variability of lumefantrine uptake and its long half life render it liable to selection pressure if sub-therapeutic concentrations prevail for long periods. Recommended milk or high fat diet to improve its bioavailability may not be available in resource limited settings. In Mwebaza et al ., 2013, our health volunteer crossover bioavailability study preceding the planned patients study, lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. Whereas both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures relative to milk. The greatly improved absorption is attributed to the little fat used to fortify maize porridge. We believe that findings in healthy adult volunteers are relevant for vulnerable African children treated with AL for P. falciparum malaria but this needs to be confirmed.
Objectives
- To describe the population pharmacokinetics of lumefantrine among under five year old children in Uganda receiving AL for uncomplicated falciparum malaria (Main study).
The described PPK profile will be correlated to treatment outcomes and will form a basis for dose recommendations. 2. To compare the effects of maize porridge plus vegetable oil versus milk on the bioavailability of lumefantrine among under five year old Ugandan children receiving artemether- lumefantrine for uncomplicated falciparum malaria (Nested Study).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 5 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of uncomplicated falciparum malaria
- •Age ≥ 6 months to ≤5 years.
- •For nested comparative bioavailability study, age >1 to ≤5 years of age, to avoid intense blood draws from younger children
- •Weight ≥5 kg.
- •For nested comparative bioavailability study, restrict evaluation to 2 weight/dose groups >5 to < 15kg and 15 to < 25kg
- •Within 10 km radius from recruitment site
- •Informed consent from parent or guardian
- •Willingness to adherence to study procedures
排除标准
- •Severe or complicated malaria "Danger signs"
- •Mixed plasmodial infection
- •Hemoglobin < 5 mg/dl
- •Weight < 5kg
- •Allergy to study medication or milk
- •Medication which known to inhibit or induce CYP3A4/5 examples ketoconazole, erythromycin, steroids, antidepressants, anticonvulsants, antiretroviral drugs.
- •Receipt of artemisinin containing compounds in the past 7 days or lumefantrine in the past 28 days
研究组 & 干预措施
Food Supplement Arm
Population PK Study will enroll 70 children receiving standard AL dose at 0, 8, 24, 36, 48, 60 hour with recommended milk or maize porridge plus oil. Both foods contain sufficient fat therefore will contribute to pool evaluations as a single cohort.
A subset, 48 children will have participated in nested comparative bio-availability study as follows Standard arm children receiving single dose with milk (12) Standard arm children receiving double dose with milk (12) Experimental arm children receiving single dose with maize porridge plus oil (12) Experimental arm children receiving double dose with maize porridge plus oil (12) The rest, 22 children will have participated exclusively in PPK, receiving appropriate single or double dose with milk similar to those in standard arm
干预措施: Food (Dietary Supplement)
Food Supplement
Population PK Study will enroll 70 children receiving standard AL dose at 0, 8, 24, 36, 48, 60 hour with recommended milk or maize porridge plus oil. Both foods contain sufficient fat therefore will contribute to pool evaluations as a single cohort.
A subset, 48 children will have participated in nested comparative bio-availability study as follows Standard arm children receiving single dose with milk (12) Standard arm children receiving double dose with milk (12) Experimental arm children receiving single dose with maize porridge plus oil (12) Experimental arm children receiving double dose with maize porridge plus oil (12) The rest, 22 children will have participated exclusively in PPK, receiving appropriate single or double dose with milk similar to those in standard arm
干预措施: Food (Dietary Supplement)
结局指标
主要结局
Pharmacokinetic (PK) exposure parameters of lumefantrine
时间窗: 28 days
Sparse pharmacokinetic data will be pooled for evaluation of both individual and population PK parameter estimates of lumefantrine using Non linear mixed effect model. Pharmacokinetic exposure will be depicted principally by area under the concentration-time curves following the last dose through to 28 days of follow up (AUC0-28). Other PK parameters portraying exposure will also be assessed alongside. These include half life (t1/2), peak concentrations (Cmax) and time to reach Cmax (Tmax), apparent clearance and volumes of distribution.
次要结局
- Relative Oral Bioavailability of lumefantrine(8 h after the first dose)
研究者
College of Health Sciences
Dr Norah Mwebaza
Makerere University