Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria.
Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive l-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of l-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for l-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria.
Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
Janneke M
JM
Brussee
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore Insitute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore.
Tsin W
TW
Yeo
National Institute of Health Research and Development-Menzies School of Health Research Malaria Research Program, Timika, Indonesia.
Daniel A
DA
Lampah
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia.
Nicholas M
NM
Anstey
Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand stephen.duffull@otago.ac.nz.
Stephen B
SB
Duffull
D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000097:blood / Q000493:pharmacokinetics*; D001808:Blood Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000469:parasitology; D045853:Exhalation; D005260:Female; D015870:Gene Expression; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood* / Q000469:parasitology / Q000503:physiopathology; D008297:Male; D008365:Manometry; D008875:Middle Aged; D009569:Nitric Oxide / Q000819:agonists* / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000254:growth & development / Q000472:pathogenicity; D012720:Severity of Illness Index
D009569:Nitric Oxide; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III