Clinical trial NCT01944189: Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics and Population Pharmacokinetics
Official title: Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics of Lumefantrine and Population Pharmacokinetics of Lumefantrine Among Ugandan Children
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Malaria, Falciparum
Keywords: lumefantrine pharmacokinetics & bioavailability
Lead sponsor: Makerere University
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: Swedish International Development Cooperation Agency (SIDA)
First posted: 2013-09-17
Enrollment: 70
Sex: ALL
Minimum age (years): 6
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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

1. The population pharmacokinetic profile of lumefantrine among under five year old children in Uganda with uncomplicated falciparum malaria is not affected by demographic factors.
2. 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.

Detailed description: 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

1. 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).

This study will establish whether it is possible to recommend fortification of carbohydrate rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine , if milk is not available in resource limited setting during artemether lumefantrine treatment for uncomplicated malaria.

Mani sub-study (1). A single centre open-label prospective non-comparative pharmacokinetic study will be carried out at the Department of Pharmacology \& Therapeutics, Makerere University College of Health Sciences, at Mulago Hospital Complex, Kampala, Uganda. Study will include children (less than 5 years, n=70) diagnosed with uncomplicated falciparum malaria destined to receive standard fixed-weight-based six-dose regimen of artemether-lumefantrine for 3 days on outpatient basis . A full population pharmacokinetic design will be employed to obtain sparse venous plasma samples from participants at scheduled periods during a 28 day follow up period. Each participant will provide between 1 to 8 samples during the 28 day follow up period. Venous plasma levels of lumefantrine (L) and its metabolite desbutyl-lumefantrine (DL) will be determined using liquid chromatography and mass spectrometry tandem (LCMS/MS) at the Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. Outcome variables will be pharmacokinetic (PK) exposure parameters of L and DL. Sparse PK data will be pooled for evaluation of both individual and population PK parameter estimates of lumefantrine using NONMEM. Impact of patients' explanatory variables on PK parameters will be assessed. Secondary outcomes will include be adverse events and day 28 treatment outcome.

Nested sub-study (2), is a comparative bioavailability study to compare lumefantrine bioavailability after the first oral dose of AL among pediatric patients receiving standard care. Forty eight out of the 70 under five year old children with uncomplicated malaria will be randomized to receive AL with either milk (n=24) or local maize porridge plus oil (n=24). Venous plasma concentrations (1 ml, whole blood) will be obtained up to 8 hours (at 0, 1, 1.5, 2, 3, 4, 6, 8) after the first using an intensive pharmacokinetic sampling design. Thereafter 1 to 8 sparse venous blood samples will be obtained during a 28 day follow up period to contribute to the PPK study pool. Primary Pharmacokinetic endpoints and outcomes will be exposure parameters after first dose, up to 8 h. Peak concentrations (Cmax) and early exposure (AUC0-8h) will be used for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Secondary end points will be day 28 in follow up with lumefantrine PK exposure (AUC0-28d and AUC0-∞) and day 28 treatment outcomes as secondary outcomes. Correlation of overall exposure (AUC0-28d and AUC0-∞) to clinical and parasitological response to AL treatment will be explored.

Eligibility criteria: Inclusion criteria:

* 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

Exclusion criteria:

* 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

Primary outcomes:
measure: Pharmacokinetic (PK) exposure parameters of lumefantrine
timeFrame: 28 days
Secondary outcomes:
measure: Relative Oral Bioavailability of lumefantrine
timeFrame: 8 h after the first dose
Other outcomes:
measure: Malaria treatment outcome (clinical and parasitological response)
timeFrame: 28 days
measure: Adverse events
timeFrame: 28 days
Locations:
city: Kampala
country: Uganda
facility: Department of Pharmacology & Therapeutics, MakCHS, Mulago Hospital Complex
Study officials:
affiliation: • Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences (MakCHS), Uganda
name: Norah Mwebaza, MBChB M Sc
role: PRINCIPAL_INVESTIGATOR
affiliation: Div Infectious Diseases, Karolinska Institutet (KI) , Sweden
name: Urban Hellgren, MD PhD
role: STUDY_CHAIR
affiliation: Dep Lab Medicine, Div Clinical Pharmacology, KI
name: Lars L Gustaffson, MD PhD
role: STUDY_CHAIR
affiliation: Department of Pharmacology and Therapeutics, MakCHS, Kampala, Uganda
name: Paul Waako, PhD
role: STUDY_CHAIR
affiliation: Department of Pharmacology and Therapeutics, MakCHS, Kampala, Uganda
name: Celestino Obua, PhD
role: STUDY_CHAIR
References:
citation: Mwebaza N, Jerling M, Gustafsson LL, Obua C, Waako P, Mahindi M, Ntale M, Beck O, Hellgren U. Comparable lumefantrine oral bioavailability when co-administered with oil-fortified maize porridge or milk in healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Jul;113(1):66-72. doi: 10.1111/bcpt.12065. Epub 2013 Apr 6.