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Antimicrobial Agents and Chemotherapy, December 2008, p. 4381-4387, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00421-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of L-Arginine in Adults with Moderately Severe Malaria{triangledown}

Tsin W. Yeo,1* Indri Rooslamiati,2 Retno Gitawati,2 Emiliana Tjitra,2 Daniel A. Lampah,3,4 Enny Kenangalem,3,4 Yvette R. McNeil,1 Richard N. Price,1,5,6 Nicholas M. Anstey,1,6 and Stephen B. Duffull7

International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia,1 National Institute of Health Research and Development, Jakarta, Indonesia,2 National Institute of Health Research and Development-Menzies School of Health Research Malaria Research Program,3 District Ministry of Health, Timika, Papua, Indonesia,4 Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom,5 Division of Medicine, Royal Darwin Hospital,6 School of Pharmacy, University of Otago, Dunedin, New Zealand7

Received 29 March 2008/ Returned for modification 22 June 2008/ Accepted 28 September 2008

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the Km of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.

* Corresponding author. Mailing address: Menzies School of Health Research, P.O. Box 41096, Casuarina, NT 0810, Australia. Phone: (15) 8922 8197. Fax: (15) 8927 5187. E-mail: tsin.yeo{at}menzies.edu.au

{triangledown} Published ahead of print on 6 October 2008.

Antimicrobial Agents and Chemotherapy, December 2008, p. 4381-4387, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00421-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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