Journal Article

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

Racette, Susan B, Stratford, Robert E, Thies Dakkota, Coggan, Andrew R, Peterson, Linda R

2020

Overview

PurposeThe 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.MethodsLinear 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.ResultsA 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.ConclusionsExtension of the present first-generation model, to ultimately optimize NO3− dose versus pharmacological effects, is warranted.

• Publisher: Springer Nature B.V
• Subject: Body weight / Clinical trials / Metabolites / Muscle contraction / Nitrogen dioxide / Pharmacokinetics