Study Groups

Analysing PK/PD data to identify inadequate drug exposure and inform dosage

A pooled lumefantrine pharmacokinetic-pharmacodynamic (PK/PD) analysis is being conducted to evaluate the exposure to lumefantrine in different populations to identify patient groups (such as young children and pregnant women) at particular risk of treatment failure. Further, to identify the pharmacokinetic-pharmacodynamic relationship of lumefantrine in the treatment of uncomplicated falciparum malaria. The group will use the the population PK-PD analysis and model developed to conduct in-silico dose optimisations.

Publication details:

WWARN Lumefantrine PK/PD Study Group. 'Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data'. Published in BMC Medicine 2015. 13:227  doi:10.1186/s12916-015-0456-7.

Follow-on analysis:

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. Published in PLOS Medicine June 2018. 15 (6): 1-27. Doi: 10.1371/journal.pmed.1002579  PMID: 29894518

A pooled analysis of Plasmodium falciparum gametocyte carriage

The purpose of this Study Group is to assess the risk factors for treatment failure associated with gametocyte carriage and clearance across a range of endemic settings and antimalarial drug treatments. To achieve this requires a standardised database and a set of metrics which are derived in a systemic manner. Data within the WWARN Data Centre provide an excellent opportunity. 

Study published on 24 July 2016:

WWARN Gametocyte Study Group. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Medicine 2016 14:79 DOI: 10.1186/s12916-016-0621-7

The AL Dose Impact Study Group was first established in 2011. The Study Group first met in December 2011 at the ASTMH Annual Meeting to discuss the Study Group governance and publication policy. The Study Group closed in March 2013. The latest results were presented at the 2014 ASTMH Annual Meeting in New Orleans, USA.

The artemether-lumefantrine (AL) Dose Impact Study Group found that the efficacy of the combination was lowest in young children from Asia and young underweight children from Africa, suggesting that a higher dose regimen should be evaluated in these groups. The manuscript for this Study Group was published by the Lancet Infectious Diseases in March 2015: The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. 

Briefly, data from 66 clinical trials (n=15,529) conducted between 1998 and 2012, including eight unpublished studies and 58 published, studies representing 59 per cent of the targeted published literature on AL treatment were shared with WWARN. 61 studies (14,327 patients) were included in the final analysis. Of those patients included in the final analysis, 82.4 per cent were from Africa, 16.5 per cent from Asia and 1.1 per cent from South America.

Download a presentation from the AL Dose Impact Study Group.

Analysing PK/PD data to identify inadequate drug exposure and inform antimalarial dosage

A pooled pharmacokinetic/pharmacodynamics (PK/PD) analysis of amodiaquine (AQ) is complete. The analysis focused on a population pharmacokinetic/pharmacodynamic model of amodiaquine and its active metabolite desethyl-amodiaquine in patients who received either amodiaquine as a monotherapy regimen or in combination with artesunate. The full covariate analysis explored the effects of fixed versus loose dose formulations, age, nutrition status, baseline parasitemia and sample matrix.

Publication: WWARN Amodiaquine PK Study Group. Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis to Optimise Dosing. Denti et al. Antimicrobial Agents and Chemotherapy. 2018, Sept 24:62(10)

Effect of DP mg/kg dosing strategies on the risk of treatment failure

A pooled analysis to assess the impact of weight adjusted (mg/kg) dose variations of dihydroartemisinin-piperaquine (DP) on the therapeutic efficacy of both drugs combined. The Study Group assessed if the dose of piperaquine administered to patients was a risk factor for recrudescence, (recurrence of symptoms).

The Study Group closed in March 2013. A paper was published in Plos Medicine in December 2013. Results from this study group provided evidence for the revised recommendations for optimal use of artemisinin combination therapies included in the updated WHO ‘Guidelines for the Treatment of Malaria in June 2015.

Related publications:

The WorldWide Antimalarial Resistance Network (WWARN) DP Study Group (2013) The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLOS Med 10(12): e1001564. doi:10.1371/journal.pmed.1001564

Parasite clearance after treatment with an artemisinin monotherapy or ACT

This Study Group characterises parasite clearance stratified by location, treatment and time and to find optimal restricted sampling schemes for clearance estimation and provides baseline information on parasite clearance.

The latest study, ‘Baseline parasite clearance data in uncomplicated falciparum malaria after treatment with an artemisinin derivative alone or in combination’, has been submitted to Malaria Journal and is currently under review.

Related publications:

Flegg JA, Guerin PJ, Nosten F et al. Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives. Malaria Journal, 2013. Doi: 10.1186/1475-2875-12-411.  PMID: 24225303

WWARN Parasite Clearance Study Group ‘Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis’ Published in Malaria Journal 2015. DOI:10.1186/s12936-015-0874-1

Determining the optimal Artemether-lumefantrine antimalarial dosing for young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

Analysing PK/PD data to identify inadequate drug exposure and inform dosage

A pooled piperaquine pharmacokinetic analysed the exposure to piperaquine in different populations in order to identify patient groups at particular risk of treatment failure, such as young children and pregnant women. The model can be used to optimise the dose in these vulnerable populations in order to give all patients an equal chance of cure.

The pharmacokinetic analysis has been finalised and published.

A pooled analysis on the relationship between K13 molecular marker and parasite clearance data. The Study Group closed to new participants in December 2015. The analysis was completed between 2016–2018 and the group published in January 2019. WWARN K13 Genotype-Phenotype Study Group. Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis. BMC Medicine. January 17, 2019.

Baseline information on parasitological response to ACTs in Africa

A pooled analysis to assess the baseline early parasitological response after artemisinin combination therapy (ACT) treatments in sub-Saharan Africa. The analysis compiles the day 3 parasite positivity rates (PPR) in patients with uncomplicated Plasmodium falciparum malaria enrolled in ACT clinical efficacy trials.

The Study Group closed in March 2013. A draft manuscript has been finalised and shared with the Study Group members in February 2015. The study was published in BMC Medicine in September 2015.

Publication details: 

WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data. BMC Medicine 2015, 13:212 doi:10.1186/s12916-015-0445-x

Effect of AS-AQ mg/kg dosing strategies on the risk of treatment failure

A pooled analysis to assess the impact of weight adjusted (mg/kg) dose variations of artesunate-amodiaquine (AS-AQ) on therapeutic efficacy of both drugs combined. The Study Group assessed if the dose of amodiaquine administered to the patients was a risk factor for recrudescence(recurrence of symptoms). The results are expected to be published in the BMC Medicine at the end of March 2015.

The study group closed in March 2013. The paper was published in March 2015. 

Publiction details: 

The Worldwide Antimalarial Resistance Network (WWARN) AS-AQ Study Group. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Medicine 2015 13:66. Published 31 March 2015 doi: 10.1186/s12916-015-0301-z.

A population pharmacokinetic/pharmacodynamic model of pyrimethamine and sulfadoxine in participants who received either sulfadoxine-pyrimethamine (SP) as a monotherapy regimen or in combination with artesunate is being conducted. The full covariate analysis will explore the effects of participants and/or environmental factors that could influence the pharmacokinetics of pyrimethamine and/or sulfadoxine.

The data collection/curation is complete and the pharmacokinetic-pharmacodynamic analysis is currently ongoing to prepare for publication.

Role of candidate molecular markers of lumefantrine and amodiaquine resistance

The Artesunate-Amodiaquine/Artemether Lumefantrine (AS-AQ/AL) Molecular Marker Study Group demonstrated that if patients are infected with malaria parasites that carry particular mutations in genes pfcrt and pfmdr1, they are at higher risk of treatment failure after artemether-lumefantrine (AL).

Related publications:

Venkatesan M, et al. Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine.  Am J Trop Med Hyg. 2014 Oct;91(4):833-43. doi: 10.4269/ajtmh.14-0031.