Application of a Stable Isotope Technique for the Bioequivalency Study of Two Transdermal Nitroglycerin Systems

A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of (15)N-labeled nitroglycerin ((15)N-NTG) solution. The total amount of NTG transdermally absorbed (AUC x CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 plus minus 3.3 versus 8.1 plus minus 2.6 mg; p = 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 plus minus 3.1 versus 10.8 plus minus 3.1 mg; p = 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 plus minus 0.21 mg h(minus sign1) at 1 h for the experimental system and 0.41 plus minus 0.15 mg h(minus sign1) at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and (15)N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of (15)N-NTG for all participating subjects. The momentary changes of clearance, estimated from (15)N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.