Janneke M. Brussee, Tsin W. Yeo, Daniel A. Lampah, Nicholas M. Anstey, Stephen B. Duffull

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 decreased plasma l-arginine concentrations, 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 ten 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 hyperaemia-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 time intervals would prolong the time within therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule-dependent. Further studies are necessary to characterise the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria.