Joel Tarning (1,2), Ilse C E Hendriksen (1,2), Deogratius Maiga (3), Martha M Lemnge (3), George Mtove (4), Samwel Gesase (5), Hugh Reyburn (6), Niklas Lindegardh (1,2), Nicholas P J Day (1,2), Lorenz von Seidlein (7), Arjen M Dondorp (1,2), Nicholas J White (1,2)
1) Mahidol-Oxford Tropical Research Unit, Faculty of Tropical Medicine, Bangkok, Thailand. 2) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. 3) National Institute for Medical Research, Tanga Medical Research Centre, Tanga, Tanzania. 4) National Institute for Medical Research, Amani Centre, Tanga, Tanzania. 5) National Institute for Medical Research, Korogwe Research Station, Tanga, Tanzania. 6) London School of Tropical Medicine and Hygiene, London, United Kingdom. 7) Menzies School of Health Research, Casuarina, NT, Australia.
Objectives: Parenteral artesunate is the drug of choice for treatment of severe malaria. The pharmacokinetic properties of intramuscular artesunate have not been studied in the main treatment group who carry the highest mortality; critically ill children with severe malaria. Although artesunate is superior, parenteral quinine is still widely used. The objectives were to characterize the pharmacokinetic-pharmacodynamic properties of quinine, artesunate and dihydroartemisinin (the active metabolite of artesunate) in children with severe malaria in Tanzania and recommend practical dosing regimens.
Methods: A nested population pharmacokinetic study was conducted, as part of a large outcome trial [1], in Tanzanian children aged 4 months to 11 years. They received a standard body weight-based dose of quinine (n=75) [2] or artesunate (n=70) [3]. Sparse capillary data were characterized using nonlinear mixed-effects modeling and outcome modeled with a time-to-event approach. The final population pharmacokinetic models were used for Monte-Carlo simulations and dose optimization.
Results: Observed mortality was 12.9% [CI.6.05-23.0%] and 17.3% [CI.9.57-27.8%] after artesunate and quinine dosing, respectively; relative reduction of 25.8% for artesunate treatment compared with quinine treatment. A zero-order absorption model with one-compartment disposition pharmacokinetics described all the drugs adequately. Body weight as an allometric function was a significant covariate in all models. An exposure-effect relationship was established for quinine with cumulative AUC modulating the hazard of mortality. No exposure-effect relationship could be established for artesunate/dihydroartemisinin in the pharmacokinetic cohort. Simulations using the final population pharmacokinetic models indicated a reduced quinine, artesunate and dihydroartemisinin exposure at lower body weights after a standard weight-based dosing.
Conclusions: Artesunate/dihydroartemisinin and quinine pharmacokinetics were adequately described. A loading dose of quinine is recommended and resulted in adequate drug levels for all body weights with no evidence of dose related drug toxicity. Children at lower body weights had reduced artesunate/dihydroartemisinin exposure and the final model was used to develop a practical dosing table for intramuscular artesunate in the treatment of severe malaria.
References:
[1] Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Dondorp AM, et. al., Lancet. 2010 Nov 13;376(9753):1647-57.
[2] The population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe falciparum malaria. Hendriksen I.C.E., et. al., Antimicrobial Agents & Chemotherapy. 2013 57(2):775.
[3] Population pharmacokinetics of artesunate and dihydroartemisinin following intramuscular artesunate in African children with severe falciparum malaria. Hendriksen I.C.E., et. al., Clinical Pharmacology & Therapeutics – in press
Reference: PAGE 22 (2013) Abstr 2835 [www.page-meeting.org/?abstract=2835]
Poster: Infection