Population Pharmacokinetics of Nitroglycerin and of Its Two Metabolites After a Single 24-Hour Application of a Nitroglycerin Transdermal Matrix Delivery System

Abstract

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 (Vc/F 6 L [45]), V2/F 78 L [51]), and V3/F 29 L [40]), respectively). Mean calculated elimination half-lives (t1/2+/-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).

Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects

“…[10][11][12] A growing number of transdermal systems based on the matrix technology were developed for the delivery of steroid hormones and other drugs such as buprenorphine and nitroglycerin. [24][25][26] To determine the pharmacokinetics, tolerability, and performance of the novel matrix transdermal delivery system of fentanyl, a total of 20 healthy male subjects received repeated 72-hour applications of 50 µg/h of fentanyl as the novel matrix and reservoir formulations in a randomized, 2-way crossover study. Patch adherence, skin irritation, and amounts of fentanyl delivered were evaluated.…”

Nitroglycerin alters matrix remodeling proteins in THP-1 human macrophages and plasma metalloproteinase activity in rats

“…The concentrations of 1,2-GDN and 1,3-GDN observed clinically were 0.3–119.5 ng/ml and 0.5–42.2 ng/ml, respectively [38; 41; 43; 44; 45]. In the present study, we added NTG at 10 nM or 2.27 ng/ml in the incubation medium on days 1, 4 and 7.…”

“…After transdermal NTG administration in humans, plasma concentrations ranged from 0.44–40.7 nM or 0.1–9.24 ng/ml [36; 37; 38; 39; 40; 41; 42]. The concentrations of 1,2-GDN and 1,3-GDN observed clinically were 0.3–119.5 ng/ml and 0.5–42.2 ng/ml, respectively [38; 41; 43; 44; 45].…”

“…For example, in patients on long-term intravenous NTG infusions at doses ranging from 1.3 to 12.0 mg/hour for 1 to 16 days, Torfgard et al [43] observed plasma concentrations of 0.8 to 894.5 ng/ml for NTG, undetected to 119.5 ng/ml (for 1,2-GDN), and 0.8–42.2 ng/ml (for 1,3-GDN), respectively. The composite plasma concentrations observed after transdermal NTG administration, at doses of 5 to 105 mg per day, ranged from 0.1 to 9.24 ng/ml (NTG), 0.3–3.5 ng/ml (1,2-GDN), and 0.5–0.8 ng/ml (1,3-GDN), respectively [36; 38; 39; 40; 41; 42; 44; 45]. The plasma concentrations observed in the present study, i.e., NTG: 0.3 to 0.7 ng/ml, 1,2-GDN: 2 to 23 ng/ml, and 1,3-GDN: 1.2 –11 ng/ml, were well within these clinically observed values.…”

Opportunities and Challenges Related to the Implementation of Model‐Based Bioequivalence Criteria

“…By simultaneously fitting GTN and its two metabolites (1,2‐GDN and 1,3‐GDN) with a compartmental population PK model, one can theoretically characterize the rate and extent at which these transdermal formulations deliver their active ingredient. Using this method, it was proposed that a follow‐on formulation was equivalent to the previous reference product . One drawback of this proposed analysis was that the two formulations were not simultaneously fitted; therefore, differences could be attributed to drug‐specific parameters (those associated with distribution, metabolism, and elimination) instead of exclusively to formulation‐dependent parameters (those associated with rate and extent of exposure).…”