New collaboration to distinguish inadequate lumefantrine exposure from resistance

The importance of antimalarial treatment dosing is often underestimated in current strategies to control and eventually eliminate malaria. Dosage recommendations tend to be for the lowest doses that produce ‘satisfactory’ results, based largely on pre-licensing studies which are necessarily limited in both sample size and populations studied, and lack the accumulated experience of widespread, post-marketing field use. WWARN is combining available pharmacokinetic (PK) and treatment response (pharmacodynamics (PD)) data to define how frequently treatment failure could be explained by inadequate drug exposure and to identify any patient factors associated with inadequate drug exposure.  

Over the past five months the WWARN Pharmacology Module has worked with researchers from around the world to collate and curate data from 20 studies in which 7529 lumefantrine samples were collected from 1851 malaria patients and 73 healthy volunteers.  The study locations include Thailand, Uganda, Tanzania, Laos, Cambodia, Benin, South Africa and the United States. A statistical analysis plan is being developed with collaborators to overcome the challenges of combining data collected using a variety of methods and optimise the use of available data.

WWARN’s first pooled analysis focuses on the pharmacokinetics (PK) and pharmacodynamics (PD) of lumefantrine, which is one of the most widely used partner drugs in artemisinin-based combination therapies (ACTs). PK and PD data from individual studies are insufficient to accurately define the minimum drug exposure required to achieve an adequate clinical and parasitological response, particularly in special-risk groups. Lower levels of lumefantrine exposure have been described in published studies of young children, pregnant women, smokers, patients weighing over 80kg, or when artemether-lumefantrine is taken unsupervised, without fat, or with mefloquine. Prof Karen Barnes, Module Head, Pharmacology, explains: “Combining and analysing individual PK and PD data on such a large scale is one of the most effective ways of uncovering trends. In this study our aim is to accurately define the lumefantrine concentrations that need to be achieved and sustained to ensure a cure – and how frequently lower concentrations (rather than antimalarial resistance) explain treatment failures. We may then be able to determine whether there are any patient groups in which, for example, age, pregnancy status or HIV co-infection might lower lumefantrine exposure and therefore compromise the therapeutic response. ”

The study also aims to validate the use of a lumefantrine concentration at a single timepoint as a simple surrogate measure of whether drug exposure is adequate (therapeutic) or too low (sub-therapeutic). Some therapeutic efficacy trials have used the Day 7 lumefantrine blood concentrations as such a measure, and have published cut-off concentrations that range widely from 170 ng/mL to 500 ng/mL. However, the wide variation between these threshold concentrations and the high proportion of patients cured despite measured lumefantrine concentrations being below these levels, suggests that this threshold could be better defined. The planned pooled analysis is designed to validate a simple measure of drug exposure.

“We’d like to thank everyone who contributed their lumefantrine data to this collaborative analysis”, added Prof Barnes.  “This is the first and largest PK PD pooled analysis of its kind, so our aim for the future is to replicate the study with other antimalarials. This is crucial for differentiating true resistance from inadequate drug exposure.  It is only by working together and combining data that we can make the most of available data and fully understand which key factors influence drug exposure. This knowledge has the potential for delaying antimalarial resistance by improving dosing.”

The study will be published later this year.  For further information, contact WWARN Clinical Pharmacology Head of Statistics, Kasia Stepniewska at kasia.stepniewska@wwarn.org.