Quantitative Systems Pharmacology Model of NO Metabolome and Methemoglobin Following Long-Term Infusion of Sodium Nitrite in Humans

K Vega-Villa, R Pluta, R Lonser, S Woo, K Vega-Villa, R Pluta, R Lonser, S Woo

Abstract

A long-term sodium nitrite infusion is intended for the treatment of vascular disorders. Phase I data demonstrated a significant nonlinear dose-exposure-toxicity relationship within the therapeutic dosage range. This study aims to develop a quantitative systems pharmacology model characterizing nitric oxide (NO) metabolome and methemoglobin after sodium nitrite infusion. Nitrite, nitrate, and methemoglobin concentration-time profiles in plasma and RBC were used for model development. Following intravenous sodium nitrite administration, nitrite undergoes conversion in RBC and tissue. Nitrite sequestered by RBC interacts more extensively with deoxyhemoglobin, which contributes greatly to methemoglobin formation. Methemoglobin is formed less-than-proportionally at higher nitrite doses as characterized with facilitated methemoglobin removal. Nitrate-to-nitrite reduction occurs in tissue and via entero-salivary recirculation. The less-than-proportional increase in nitrite and nitrate exposure at higher nitrite doses is modeled with a dose-dependent increase in clearance. The model provides direct insight into NO metabolome disposition and is valuable for nitrite dosing selection in clinical trials.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e60; doi:10.1038/psp.2013.35; published online 31 July 2013.

Figures

Figure 1
Figure 1
Nitrite–hemoglobin interactions in RBC.
Figure 2
Figure 2
Observed and model-predicted concentration–time profiles for nitrite and nitrate in plasma and RBC and methemoglobin after administration of maximal-tolerated dose (266.9 μg/h/kg) for 48 h.
Figure 3
Figure 3
The quantitative systems pharmacology model of nitric oxide metabolome and methemoglobin. Dotted arrows and open boxes indicate stimulation process. Shaded compartments represent variables that were experimentally measured and open compartments represent variables with no measurements.
Figure 4
Figure 4
Observed and model predicted concentration–time profiles for plasma nitrate (a) and nitrite (b) in a subject with evidence of the entero-salivary circulation.
Figure 5
Figure 5
Goodness of fit plots for population and individual predictions including observed vs. population-predicted (a) and individual-predicted concentrations (b); and individual weighted residuals vs. individual predicted concentrations (c), or time (d). Solid lines represent the line of unity.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3731826/bin/psp201335i1.jpg

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