TY - JOUR
T1 - Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population
AU - Coggan, Andrew R.
AU - Racette, Susan B.
AU - Thies, Dakkota
AU - Peterson, Linda R.
AU - Stratford, Robert E.
N1 - Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Nitric oxide
KW - isokinetic dynamometry
KW - nitrate
KW - nitrite
KW - pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85094878474&partnerID=8YFLogxK
U2 - 10.1007/s11095-020-02959-w
DO - 10.1007/s11095-020-02959-w
M3 - Article
C2 - 33140122
AN - SCOPUS:85094878474
SN - 0724-8741
VL - 37
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 12
M1 - 235
ER -