Pharmacokinetics of L-arginine in adults with moderately severe malaria.
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 K(m) of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.
Menzies School of Health Research, P.O. Box 41096, Casuarina, NT 0810, Australia. tsin.yeo@menzies.edu.au
Tsin W
TW
Yeo
Indri
I
Rooslamiati
Retno
R
Gitawati
Emiliana
E
Tjitra
Daniel A
DA
Lampah
Enny
E
Kenangalem
Yvette R
YR
McNeil
Richard N
RN
Price
Nicholas M
NM
Anstey
Stephen B
SB
Duffull
D000293:Adolescent; D000328:Adult; D000818:Animals; D001120:Arginine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009569:Nitric Oxide / Q000096:biosynthesis; D010963:Plasmodium falciparum; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
D009569:Nitric Oxide; D001120:Arginine