Malaria, Falciparum Clinical Trial
Official title:
Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics of Lumefantrine and Population Pharmacokinetics of Lumefantrine Among Ugandan Children
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.
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.
;
Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Supportive Care
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