Specific pharmacokinetic interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum

Abstract

The blood schizontocidal activity of lumefantrine, monodesbutyl-benflumetol (DBB) and a 999:1 combination of both compounds has been investigated in 26 fresh isolates of Plasmodium falciparum from northwestern Thailand, using the WHO standard protocol Mark II for determining the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation (GMCOC) were 943.2 nM for lumefantrine, 146.3 nM for DBB and 182.2 nM for the 999:1 combination of lumefantrine and DBB. The EC(50) values were 27.3 nM for lumefantrine, 5.7 nM for DBB, and 16.5 nM for the combination, and the EC(90) values 163.1 nM for lumefantrine, 44.1 nM for DBB, and 78.3 nM for the combination. Despite the very low concentration in the combination, DBB exerted significant synergistic activity with lumefantrine that was strongest at the EC(90) and EC(99) levels. Correlation analysis indicates that DBB is the leading determinant for the activity of the combination.

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

“…This effect was independent of CQ sensitivity. The lack of an in vitro interaction between DBL and lumefantrine appears to contradict previous reports of synergy in field isolates of P. falciparum using limited numbers of drug combinations (23,24). However, the synergy between DBL and dihydroartemisinin that we observed using dual methods of isobolographic data analysis parallels data from studies of field isolates of P. vivax (13) and P. falciparum (16).…”

“…The two laboratory-adapted strains of P. falciparum were more sensitive in vitro to DBL than to lumefantrine, consistent with data from previous studies using field isolates (17,23,24). This effect was independent of CQ sensitivity.…”

“…Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).…”

“…There is evidence of in vitro synergy between lumefantrine and DBL against P. falciparum but at ratios (999:1 and 995:5) that were presumably selected at a time when plasma concentrations of DBL were assumed to be very much lower than those of the parent compound (23,24). Interactions between DBL and artemisinin were assessed in a study of schizont maturation in Thai P. vivax field isolates in which antagonism was found at low concentrations and apparent synergy was found at much higher concentrations (13).…”

“…Because of its relative in vitro potency and evidence of low cardiac toxicity (26), DBL has been suggested as an antimalarial drug in its own right (24). There is, however, a need for a further assessment of its interactions with other antimalarial drugs, especially lumefantrine and the artemisinin derivatives, in strains of P. falciparum of differing drug sensitivities.…”