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Clinical Trial
. 2001 Feb;45(2):509-16.
doi: 10.1128/AAC.45.2.509-516.2001.

Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria

S Krishna  1 , T Planche, T Agbenyega, C Woodrow, D Agranoff, G Bedu-Addo, A K Owusu-Ofori, J A Appiah, S Ramanathan, S M Mansor, V Navaratnam
Affiliations
Clinical Trial

Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria

S Krishna et al. Antimicrob Agents Chemother. 2001 Feb.

Abstract

We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 and P = 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P < 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.

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Figures

FIG. 1
FIG. 1
Mean ± standard error of the mean change in parasitemia after admission for patients in group I (triangles), group II (squares), and group III (circles).
FIG. 2
FIG. 2
(a) Plasma ARS-versus-time profiles after i.v. administration of ARS. (b) Plasma ARS-versus-time profiles after i.r. administration of ARS.
FIG. 3
FIG. 3
Relative bioavailability of DHA compared with dose of i.r. ARS.
See this image and copyright information in PMC

References

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