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Antimicrobial Agents and Chemotherapy, February 2001, p. 509-516, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.509-516.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Bioavailability and Preliminary Clinical Efficacy of Intrarectal Artesunate in Ghanaian Children with Moderate Malaria

Sanjeev Krishna,1,* Tim Planche,1 Tsiri Agbenyega,2,3 Charles Woodrow,1 Dan Agranoff,1 George Bedu-Addo,3 Alex K. Owusu-Ofori,3 John Adabie Appiah,3 Surash Ramanathan,4 Sharif M. Mansor,4 and Visweswaran Navaratnam4

Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom1; Department of Physiology, University of Science and Technology, School of Medical Sciences,2 and Departments of Child Health and Medicine, Komfo-Anokye Teaching Hospital,3 Kumasi, Ghana; and University Sains Malaysia, 1800 USM, Pulau Pinang, Malaysia4

Received 14 July 2000/Returned for modification 17 October 2000/Accepted 12 November 2000

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.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terr., London SW17 ORE, United Kingdom. Phone: (020) 8725 5827. Fax: (020) 8725 3487. E-mail: s.krishna{at}sghms.ac.uk.

Antimicrobial Agents and Chemotherapy, February 2001, p. 509-516, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.509-516.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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