Open Access Research

Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults

Pauline Byakika-Kibwika123*, Mohammed Lamorde12, Jonathan Mayito3, Lillian Nabukeera1, Harriet Mayanja-Kizza13, Elly Katabira13, Warunee Hanpithakpong4, Celestino Obua5, Nadine Pakker3, Niklas Lindegardh46, Joel Tarning46, Peter J de Vries7 and Concepta Merry123

Author Affiliations

1 Infectious Diseases Institute, Makerere University, P. O. Box 22418, Kampala, Uganda

2 Department of Pharmacology and Therapeutics Trinity College, Dublin, Ireland

3 Infectious Diseases Network for Treatment and Research in Africa, Kampala, Uganda

4 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

5 Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, Kampala, Uganda

6 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK

7 Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, Netherlands

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Malaria Journal 2012, 11:132  doi:10.1186/1475-2875-11-132

Published: 27 April 2012

Abstract

Background

Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.

Methods

Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134).

Results

All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8–24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020–164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290–111256) ng·h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670–9530) ng/mL, with Tmax of 0.14 (0.6 – 6.07) hours and T1/2 of 1.31 (0.8–2.8) hours. Dihydroartemisinin AUC was 3492 (2183–6338) ng·h/mL. None of the participants reported adverse events.

Conclusions

Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.

Keywords:
Pharmacokinetics; Pharmacodynamics; Intravenous; Artesunate; Severe malaria