Pharmacokinetics of L-arginine after intravenous infusion in adults with moderately severe malaria

Background: Plasma L-arginine is a naturally occurring amino acid that has been found to be reduced in patients with malaria to concentrations below the equilibrium constant (Km) of the cationic amino acid transporter (CAT) needed for intracellular transport and may limit cellular nitric oxide (NO) production.

Aim: To develop a pharmacokinetic model for L-arginine in adults with moderately severe malaria, quantify pharmacokinetic parameter values, between subject variability and to evaluate the influence of covariates on these parameters.

Methods: L-arginine was given by intravenous infusion over 30 minutes to 3 groups of 10 adults with moderately severe malaria with each group receiving 3, 6 or12 grams. Serial plasma L-arginine concentrations were measured before and after infusion and covariate information obtained simultaneously. Eight to 11 concentration time points were obtained for each patient. Data were also available from control patients who had not received L-arginine.  Pharmacokinetic analysis was conducted using NONMEM and simulation performed using MATLAB.

Results: A two-compartment linear model with first order elimination with a clearance of 44.8L/h (CV=32%), volume of distribution of 24.6L (CV=19%) best described the data. The natural time course of L-arginine recovery was best described by a turn over model with a half-life of recovery of 26 hours. Weight and ethnicity were significant covariates for clearance. Simulation of various dosage regimens was performed to determine the regimen that will maintain plasma L-arginine concentration above the Km of the CAT transporter for design of a phase IIa proof of concept study. Twelve grams given over 1 hour, provides concentration above Km for 50% of patients for 2 hours and 12 grams over 6, 8 or 12 hours for 90%, 75% and 60% of patients at end of infusion.

Conclusions: The half life of exogenous L-arginine is significantly reduced in patients with malaria compared to patients with chronic cardiovascular diseases. Infusion of L-arginine to maintain plasma concentration above the Km has the potential to increase NO and improve outcomes in adults with moderately severe malaria.