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Lumefantrine
Olivo Miotto edited this page Sep 17, 2021
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Lumefantrine is an antimalarial drug which is only used as combination drug with artemether, known as artemether+lumefantrine (AL) treatment. Several studies demonstrated that polymorphisms and copy number variations of pfmdr1 gene were associated with altered parasite susceptibility to lumefantrine:
- N86Y mutation confers increased lumefantrine sensitivity (Veiga MI, et al, 2016, Nat Commun).
- Amplification of pfmdr1 gene causes reduced lumefantrine sensitivity (Sidhu AB, et al, 2006, J Infect Dis).
- Association between copy number variations and/or polymorphisms of pfmdr1 and AL treatment failure are still limited.
Since a strong evidence of lumefantrine resistance is still lacking, we do not apply phenotype predicting rules for lumefantrine.
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Since lumefantrine is a lipophilic compound, its absorption varies widely among individuals and depends on coadiministration with fat. Acute malaria patients are frequently nauseated and anorexic, making dietary adivice difficult to comply with and resulted in AL treatment failure (Ashley, et al, 2007, Trop Med Int Health).
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Fat coadministration (at least 1.2 g) with lumefantrine is required to achieved the maximum drug absorption (Ashley, et al, 2007, Trop Med Int Health).
| Reference | Method | Location/Sample size/Genetic background | Finding summary |
|---|---|---|---|
| Duraisingh MT, Roper C, Walliker D, Warhurst DC. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum.Mol Microbiol. 2000;36(4):955-61. | -Lumefantrine sensitivity was assessed by hypoxanthine incorporation assay. - Pfmdr1 polymorphisms were detected by using PCR-RFLP. |
- K1, W2, T994, V1/S, T9/96, FC27, SL/D6, 3D7, HB3, 7G8 and W2mef lines |
Polymorphism - Parasite lines with 86Y mutations showed lower lumefantrine IC50 than the parasites with N86 wild-type allele. |
| Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S, et al. Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis. 2006;42(11):1570-7. | - A prospective study of AL treatment, the follow-up period was 42 days. - Pfmdr1 copy number was measured by using real-time PCR. - In vitro drug sensitivity was performed by hypoxanthine incorporation assay. - SNPs in pfmdr1 gene were detected by using PCR-RFLP. |
- Northwest border of Thailand. - 1,273 uncomplicated malaria patients during 1995 to 2002. |
Copy number - In vitro: Geometric mean lumefantrine IC50 of the parasite isolates with multiple pfmdr1 copies (1.37 ng/ml) was 1.6-time higher than that of the isolates with single pfmdr1 copy (0.84 ng/ml). - In vivo: Recrudescence rate of the parasites with multiple pfmdr1 copies (43%) was higher than that of the isolates with single pfmdr1 copy (13%). Polymorphism - In vitro: Geometric mean lumefantrine IC50 of the parasites with pfmdr1 1042D mutation (7.8 ng/ml) was 2.16-fold lower than that of the parasites with wild-type allele (16.9 ng/ml). - Pfmdr1 polymorphisms did not correlate with artesunate IC50 and AL treatment outcomes. |
| Lim P, Alker AP, Khim N, Shah NK, Incardona S, Doung S, et al. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J. 2009;8:11. | - Amplification of pfmdr1 gene was determined by real-time PCR assay. - Lumefantrine susceptibility was determined by using hypoxanthine incorporation assay. |
- North-western Cambodia (Sampovloun in 2002 and 2003). - Total 135 patients who were treated with AL. |
Copy number - In vitro: Lumefantrine IC50 of the parasites with multiple pfmdr1 copies (44.1nM/L) was 2.04-fold higher than that of the isolates with single pfmdr1 copy (21.4 nM/L). - In vivo: There was no association between pfmdr1 copy number and clinical outcomes following AL combination treatment. |
| Baraka V, Mavoko HM, Nabasumba C, Francis F, Lutumba P, Alifrangis M, et al. Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda. PLoS One. 2018;13(2):e0191922. | - This study compared pfmdr1 haplotype of pre- and post-treatment parasite isolates in recurrent falciparum patients receiving AL treatment. - Polymorphisms of pfmdr1 were analyzed by nested-PCR followed by RFLP assay. |
- 110 recurrent patients in Congo and Uganda during 2012-2014. | - There was no significant evidence of directional selection for pfmdr1 N86 (p = 0.07) and D1246 (p = 0.6) in patients with recurrent infections treated with AL treatment. - There was marginal evidence suggesting a directional selection of pfmdr1 184F (p = 0.0555). |
| Reference | Method | Location/Sample size/Genetic background | Finding summary |
|---|---|---|---|
| Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis. 2006;194(4):528-35. | - 1 out of 2 pfmdr1 copies in lumefantrine-resistant FCB line was disrupted by using single-site cross over with plasmid containing pfmdr1 fragment and BSD marker. - The endogenous pfmdr1-5'UTR and pfmdr1-3'UTR were separated by the BSD selectable marker. |
- FCB line (Colombian strain). |
Copy number - Lumefantrine IC50 of the pfmdr1 knockdown parasites (22.8 nM) was 3.9-time lower than that of the parental FCB line (86.9 nM). -The pfmdr1 knockdown parasites also showed increased sensitivity of mefloquine, halofantrine, artemisinin and quinine, while the IC50 of chloroquine was not affected. |
| Veiga MI, Dhingra SK, Henrich PP, Straimer J, Gnadig N, Uhlemann AC, et al. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat Commun. 2016;7:11553. | - This study genetically modified PfMDR1 at amino acid residues 86 and 184 by using zinc-finger nuclease assay. - In vitro drug susceptibility was assessed by using a flow cytometry-based method |
- 2 progeny lines of 7G8 (Brazil) and GB4 (Ghana) were used. (1) NF10 line (CVIET pfcrt haplotype at codons 72-76; YF pfmdr1 haplotype at codons 86 and 184). (2) KC5 line (SVMNT pfcrt haplotype at codons 72-76; YF pfmdr1 haplotype at codons 86 and 184). |
Polymorphisms - Replacing 86Y mutant allele in NF10 and KC5 lines with N86 wild-type allele conferred approximately 3 times higher lumefantrine IC50 compared to parent lines. |
- Ashley EA, Stepniewska K, Lindegardh N, Annerberg A, Kham A, Brockman A, et al. How much fat is necessary to optimize lumefantrine oral bioavailability? Trop Med Int Health. 2007;12(2):195-200.