ABSTRACT
Recombinant human insulin-like growth factor (rhIGF-I) was evaluated in 18 healthy males to determine its effects on serum glucose, its relationship of total IGF levels to serum glucose response and dose proportionality when administered intravenously (IV) and subcutaneously (SQ). One group of six subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, 1 week apart, and three groups of four subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, and then 1 week later received 60, 120, and 90 &mgr;g kg(minus sign1) SQ of rhIGF-I, respectively. During each dosing period, placebo and then rhIGF-I was administered on two consecutive days. Intravenous and subcutaneous does of rhIGF-I demonstrated significant decreases in glucose levels as compared to placebo that did not correspond to peak total IGF levels. Sequential repeat administration of IV infusions of rhIGF-I in a single group of subjects demonstrated significant dose-dependent increases, whereas single administration of the doses in three groups of subjects failed to demonstrate dose dependency for either the IV or subcutaneous routes of administration. These findings suggest that saturation of the binding proteins and sites occurred at the lowest dose (60 &mgr;g kg(minus sign1)) evaluated.
ABSTRACT
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.
