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Antimicrobial Agents and Chemotherapy, January 2001, p. 181-186, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.181-186.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacokinetics and Pharmacodynamics of Intravenous Artesunate in Severe Falciparum Malaria

Timothy M. E. Davis,1,* Hoang Lan Phuong,2 Kenneth F. Ilett,3 Nguyen Canh Hung,4 Kevin T. Batty,1,3,dagger Vu Duong Bich Phuong,2 Shane M. Powell,1,3 Huynh Van Thien,4 and Tran Quang Binh2

Department of Medicine, University of Western Australia, Fremantle Hospital, Fremantle,1 and Department of Pharmacology, University of Western Australia, Nedlands,3 Australia, and Tropical Diseases Research Center, Cho Ray Hospital, Ho Chi Minh City,2 and Bao Loc Hospital, Bao Loc, Lam Dong Province,4 Vietnam

Received 28 February 2000/Returned for modification 26 June 2000/Accepted 23 September 2000

To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT50) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives (t1/2) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t1/2 (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups (P > 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT50 range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria.

* Corresponding author. Mailing address: Department of Medicine, University of Western Australia, Fremantle Hospital, P.O. Box 480, Fremantle 6959, Australia. Phone: (618) 9431 3229. Fax: (618) 9431 2977. E-mail: tdavis{at}cyllene.uwa.edu.au.

dagger Present address: School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia.

Antimicrobial Agents and Chemotherapy, January 2001, p. 181-186, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.181-186.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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