Population pharmacokinetics of nitroglycerin and of its two metabolites after a single 24-hour application of a nitroglycerin transdermal matrix delivery system

The purpose of this study was to assess the ability of our previously constructed pharmacokinetic (PK) model to describe nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN) plasma concentrations after a single-dose application of a GTN transdermal matrix delivery system. GTN, 1,2-GDN, and 1,3-GDN plasma concentrations were simultaneously fitted using a first-pass, mixed-order release, one-compartment PK model. Population PK parameter values were derived using an iterative two-stage methodology (IT2S). Some of the mean PK parameters estimates and their interindividual variability (CV%) were the percentage of the delivered GTN dose reaching the systemic circulation released by a first-order process A, 53% (44); the 1,2-GDN and 1,3-GDN formation rate constants, k(f1) 9 h(-1) (67) and k(f2) 0.5 h(-1) (38), respectively; the metabolite elimination rate constant, k((m)) 1 h(-1) (27); GTN, 1,2-GDN, and 1,3-GDN volumes of distribution (V-c/F 6 L [45]), V-2/F 78 L [51]), and V-3/F 29 L [40]), respectively). Mean calculated elimination half-lives (t(1/2) +/- standard deviation [SD]) for GTN and the GDN metabolites were 7 +/- 4 minutes and 33 +/- 7 minutes, respectively. The proposed PK model fitted the observed plasma concentrations of GTN, 1,2-GDN, and 1,3-GDN very well. This new transdermal matrix delivery system appears to behave pharmacokinetically in the same manner as a transdermal reservoir delivery system (Transderm-Nitro, Ciba-Geigy, Mississauga, Canada).