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http://f1000.com/8615961

by Christopher Plowe

Intrahost modeling of artemisinin resistance in Plasmodium falciparum.

S Saralamba, W Pan-Ngum,…, AM Dondorp, LJ White Proc Natl Acad Sci U S A 2011 Jan 4 108 1:397-402 PMID 21173254 DOI 10.1073/pnas.1006113108

Evaluation details:

Sections:

Genomics,Immunity to Infections,Cellular Microbiology & Pathogenesis,Parasitology,Pharmacogenomics,Pharmacokinetics & Drug Delivery,Antimicrobial Agents

Comments:

Recent reports from clinical trials conducted along the Thai-Cambodian border have provided evidence of prolonged parasite clearance times following treatment with artemisinin derivatives {1, 2}. In this study, the authors have used detailed parasite clearance and pharmacokinetic data, from clinical trials of artesunate conducted in western Cambodia and northwestern Thailand {2}, to develop and validate a mathematical model describing the stage-specific effects of artemisinins. The model predicts that the delayed parasite clearance observed in western Cambodia is most likely due to reduced susceptibility of ring-stage parasites to the drug and predicts that more frequent dosing would accelerate the clearance of artemisinin-resistant parasites. This study contributes to a better understanding of the artemisinin resistance phenotype, which will aid in conducting genome-wide association studies to identify regions of the parasite genome that may be associated with artemisinin resistance, as well as prioritization of candidate genes and polymorphisms for validation, and may also be useful for developing in vitro drug susceptibility assays that correlate better with slow parasite clearance. Widespread resistance to former first-line antimalarial drugs has led most malaria-endemic countries to change to artemisinin-based combination therapies (ACTs) as the first-line antimalarial treatment. However, clinical evidence of emerging resistance to artemisinins, in the form of significantly delayed parasite clearance times following treatment with artemisinin derivatives, has recently been reported in western Cambodia {1,2}. In this study, the authors hypothesize that the delayed parasite clearance observed in western Cambodia is due to a reduced susceptibility of the parasite ring stages to artemisinins. To test the hypothesis, they developed a mathematical model describing the parasite population dynamics by life stage and time and incorporating individual patient pharmacokinetic and pharmacodynamic data derived from participants in clinical trials of artesunate in western Cambodia (where parasite clearance times are dramatically prolonged) and northwestern Thailand (where parasite clearance times are much shorter), and used this model to infer stage-specific drug effects on parasite killing. The model benefited from using individual patient data to quantify and account for known sources of variation affecting parasite clearance, and did not assume any parasite stage-specific dose effect. The best model fits were observed for the Cambodian data when ring-stage drug susceptibility was reduced, supporting the hypothesis that the delayed parasite clearance observed in this area is due to reduced killing of the parasite ring stages. The authors also argue that reduced susceptibility of the rings stages is more consistent with the data and model output than one alternative mechanism, dormancy. As investigators search for a molecular marker of artemisinin resistance, higher priority may be warranted for candidate genes differentially expressed during the ring stages.

References:

{1} Noedl et al. N Engl J Med 2008, 359:2619-20 [PMID:19064625].

{2} Dondorp et al. N Engl J Med 2009, 361:455-67 [PMID:19641202].

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