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Antimicrobial Agents and Chemotherapy, August 2004, p. 2966-2972, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2966-2972.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Harin A. Karunajeewa,1 Kenneth F. Ilett,1,2 Kitiya Dufall, Adedayo Kemiki,3 Moses Bockarie,4 Michael P. Alpers,5 P. Hugh Barrett,1 Paolo Vicini,6 and Timothy M. E. Davis1*

School of Medicine and Pharmacology, University of Western Australia, Crawley,1 Clinical Pharmacology & Toxicology Laboratory, The Western Australian Centre for Pathology & Medical Research, Nedlands,2 Curtin University of Technology, Bentley, Australia,5 Modilon General Hospital,3 Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea,4 Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, Washington6

Received 9 February 2004/ Returned for modification 15 March 2004/ Accepted 16 April 2004

A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and {alpha}-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

* Corresponding author. Mailing address: University of Western Australia, School of Medicine and Pharmacology, 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.

Antimicrobial Agents and Chemotherapy, August 2004, p. 2966-2972, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2966-2972.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Karunajeewa, H. A., Manning, L., Mueller, I., Ilett, K. F., Davis, T. M. E. (2007). Rectal Administration of Artemisinin Derivatives for the Treatment of Malaria. JAMA 297: 2381-2390 [Abstract] [Full Text]  
  • HINTON, R. L., AUWUN, A., PONGUA, G., OA, O., DAVIS, T. M. E., KARUNAJEEWA, H. A., REEDER, J. C. (2007). CAREGIVERS' ACCEPTANCE OF USING ARTESUNATE SUPPOSITORIES FOR TREATING CHILDHOOD MALARIA IN PAPUA NEW GUINEA. Am J Trop Med Hyg 76: 634-640 [Abstract] [Full Text]  
  • Karunajeewa, H. A., Reeder, J., Lorry, K., Dabod, E., Hamzah, J., Page-Sharp, M., Chiswell, G. M., Ilett, K. F., Davis, T. M. E. (2006). Artesunate Suppositories versus Intramuscular Artemether for Treatment of Severe Malaria in Children in Papua New Guinea. Antimicrob. Agents Chemother. 50: 968-974 [Abstract] [Full Text]  
  • Woodrow, C J, Haynes, R K, Krishna, S (2005). Artemisinins. Postgrad. Med. J. 81: 71-78 [Abstract] [Full Text]  


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