Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.
BACKGROUND
Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL).


METHODS
On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested.


RESULTS
All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients.


CONCLUSIONS
The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.
Price
Ric N
RN
Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom. ricprice@doctors.org.uk
Uhlemann
Anne-Catrin
AC
van Vugt
Michele
M
Brockman
Al
A
Hutagalung
Robert
R
Nair
Shalini
S
Nash
Denae
D
Singhasivanon
Pratap
P
Anderson
Tim J C
TJ
Krishna
Sanjeev
S
White
Nicholas J
NJ
Nosten
François
F
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D000077549:Artemether; D000078102:Lumefantrine