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Population Kinetics, Efficacy, and Safety of Dichloroacetate for Lactic Acidosis Due to Severe Malaria in Children

From the Department of Physiology, University of Science and Technology, School of Medical Sciences (T. Agbenyega) and Departments of Child Health and Medicine, Komfo-Anokye Teaching Hospital (T. Agbenyega, G. Bedu-Addo, D. Ansong, A. Owusu-Ofori), Kumasi, Ghana; Department of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London, United Kingdom (T. Planche, S. Krishna); Department of Pharmaceutics, College of Pharmacy, University of Florida (V. A. Bhattaram, N. V. Nagaraja, H. Derendorf); Department of Medicine (Division of Endocrinology and Metabolism), College of Medicine, University of Florida (A. L. Shroads, G. N. Henderson, P. W. Stacpoole); Department of Statistics (A. D. Hutson) and Department of Biochemistry and Molecular Biology (P. W. Stacpoole), College of Medicine, University of Florida.

The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic-pharmacodynamic indirect-response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drug's lactate-lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.

Key Words: Dichloroacetate • malaria • lactic acidosis • population pharmacokinetics • pharmacodynamics

Address for reprints: Dr. Peter Stacpoole, Box 100226, JHMHC, Gainesville, FL 32610-0226.

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