Abstract
PURPOSE: The pharmacokinetic properties of plasma NO(3)(-) and its reduced metabolite, NO(2)(-), have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO(3)(-) ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials. METHODS: Linear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO(3)(-) and NO(2)(-) concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development. RESULTS: A population pharmacokinetic model relating NO(3)(-) and NO(2)(-) concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO(3)(-) delivery. Covariate analysis revealed intersubject variability in NO(3)(-) exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients. CONCLUSIONS: Extension of the present first-generation model, to ultimately optimize NO(3)(-) dose versus pharmacological effects, is warranted.