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 dataReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

BMC Medicine

, 13:227

Combating malaria: research, prevention and treatment

Abstract

BackgroundAchieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations.

MethodsThe WorldWide Antimalarial Resistance Network WWARN conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data.

ResultsOf 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations HR 1.59 95 % CI 1.36 to 1.85 per halving of day 7 concentrations and high baseline parasitemia HR 1.87 95 % CI 1.22 to 2.87 per 10-fold increase. Adjusted for mg-kg dose, day 7 concentrations were lowest in very young children <3 years, among whom underweight-for-age children had 23 % 95 % CI −1 to 41 % lower concentrations than adequately nourished children of the same age and 53 % 95 % CI 37 to 65 % lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % 95 % CI 38 to 49 % lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng-ml were associated with >98 % cure rates if parasitemia <135,000-μL.

ConclusionsCurrent artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng-ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children particularly those underweight-for-age; patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

KeywordsArtemether-lumefantrine Day 7 lumefantrine concentration Pharmacokinetic Pharmacodynamic Uncomplicated Plasmodium falciparum malaria Baseline parasitemia Malnutrition Early parasitological response Drug resistance Meta-analysis AbbreviationsACTArtemisinin-based combination therapy

AUCArea under the concentration-time curve

BLQBelow the limit of quantification

BMIBody mass index

CIConfidence interval

HRHazard ratio

IQRInterquartile range

LLOQLower limit of quantification

OxTRECOxford Tropical Research Ethics Committee

PCRPolymerase chain reaction

PKPharmacokinetic

PK-PDPharmacokinetic-pharmacodynamic

PRR48Parasite reduction rate at 48 hours

TIATransmission intensity area

WAZWeight-for-age Z-score

WHOWorld Health Organization

WWARNWorldWide Antimalarial Resistance Network

Electronic supplementary materialThe online version of this article doi:10.1186-s12916-015-0456-7 contains supplementary material, which is available to authorized users.

An erratum to this article is available at http:-dx.doi.org-10.1186-s12916-016-0757-5.

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Author: WorldWide Antimalarial Resistance Network WWARN Lumefantrine PK-PD Study Group

Source: https://link.springer.com/







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