Dataset Information

Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria.

ABSTRACT: The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination.

SUBMITTER: Lanaspa M

PROVIDER: S-EPMC3370785 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria.

Lanaspa Miguel M Moraleda Cinta C Machevo Sónia S González Raquel R Serrano Beatriz B Macete Eusebio E Cisteró Pau P Mayor Alfredo A Hutchinson David D Kremsner Peter G PG Alonso Pedro P Menéndez Clara C Bassat Quique Q

Antimicrobial agents and chemotherapy 20120319 6

The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, ...[more]

PMID: 22430959

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Project description:The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 ?g/ml (dispersible tablet) and 7.7 ?g/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 ?g · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria.

Dataset Information

Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria.

Publications

Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria.

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