Coggan, Andrew R.Racette, Susan B.Thies, DakkotaPeterson, Linda R.Stratford, Robert E., Jr.2023-03-302023-03-302020-11Coggan AR, Racette SB, Thies D, Peterson LR, Stratford RE Jr. Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population. Pharm Res. 2020;37(12):235. Published 2020 Nov 2. doi:10.1007/s11095-020-02959-whttps://hdl.handle.net/1805/32141Purpose: 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.en-USPublisher PolicyNitric oxideNitrateNitritePharmacokineticsIsokinetic dynamometryArticle