Janneke M. Brussee (1,2), Tsin W. Yeo (3), Daniel A. Lampah (4), Nicholas M. Anstey (3,5), Stephen B. Duffull (1)
(1) Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand, (2) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (3) International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia, (4) National Institute of Health Research and Development-Menzies School of Health Research Malaria Research Program, Timika, Indonesia, (5) Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia
Objectives: Microvascular dysfunction and the adhesion of parasitized red blood cells to the endothelium are important factors in the pathogenesis of malaria [1]. The aim of this study is to quantify the time course of the effects of adjunctive L-arginine treatment on measures of endothelial function in patients with moderately severe malaria.
Methods: Patient data has been collected for previous projects and included 73 adult patients who were suffering from moderately severe falciparum malaria [2, 3]. Thirty of these patients were included in an intervention arm and 43 in a placebo arm. Patients in the intervention arm were divided in three groups of ten different patients receiving 3 g, 6 g, or 12 g of L-arginine as a half hour infusion. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in nitric oxide (NO) concentrations and reactive hyperaemia-peripheral arterial tonometry (RH-PAT) index values. RH-PAT provides an index of endothelial function. Modelling was performed using the PPPD method [4] and the developed model was then used to explore optimal dosing regimens for L-arginine.
Results: The final PKPD model was a two-compartment PK model for arginine with endogenous production (as described by Yeo et al [3]) with two linked PD models for NO and RH-PAT. Administration of arginine resulted in immediate elevated NO concentrations and improved endothelial function in patients with moderately severe malaria. No evidence of a delay in RH-PAT was found in relation to L-arginine suggesting that constant concentrations of L-arginine may be needed to improve the duration of endothelial function. Simulations demonstrated that regimens of continuous infusion over longer time intervals could prolong the time within the therapeutic range for RH-PAT more than increasing dose amounts administered in thirty minutes.
Conclusions: In patients with moderately severe malaria adjunctive therapy with L-arginine is expected to improve endothelial function, especially within the first 24 hours of presentation when arginine and NO concentrations are significantly reduced. The optimal dosing regimen for L-arginine is likely to be administration schedule dependent. Further work is necessary to characterise the effects of continuous infusion of L-arginine on NO and microvascular reactivity in patients with severe malaria.
References:
[1] Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease pathogenesis: insights for new treatments. Nat Med. 2013;19(2):156-67
[2] Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, Darcy CJ, Granger DL, Weinberg JB, Lopansri BK, Price RN, Duffull SB, Celermajer DS, Anstey NM. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 2007; 204:2693-2704
[3] Yeo TW, Rooslamiati I, Gitawati R, Tjitra E, Lampah DA, Kenangalem E, McNeil YR, Price RN, Anstey NM, Duffull SB. Pharmacokinetics of L-arginine in adults with moderately severe malaria. Antimicrob Agents Chemother 2008; 52:4381-4387
[4] Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn 2003; 6:387-404
Reference: PAGE 23 () Abstr 3164 [www.page-meeting.org/?abstract=3164]
Poster: Drug/Disease modeling - Infection