Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population

Purpose: The pharmacokinetic properties of plasma NO₃⁻ and its reduced metabolite, NO₂⁻, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO₃⁻ 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 NO₃⁻ and NO₂⁻ 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 NO₃⁻ and NO₂⁻ concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO₃⁻ delivery. Covariate analysis revealed intersubject variability in NO₃⁻ 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 NO₃⁻ dose versus pharmacological effects, is warranted.