Pharmacokinetics and the Variability of Percutaneous Absorption

Abstract

Transdermal delivery systems have gained wide acceptance over the past decade. These systems allow more control over the surface area and, therefore, the doses delivered to a patient compared to conventional ointments and creams; however, as with ointments, the skin and not the delivery system controls the absorption rate for most drugs. The in vivo percutaneous absorption of nitroglycerin, a highly potent cardiovascular drug with good absorption characteristics, has been investigated over the course of 5 years in more than 300 subjects. Various types of delivery systems, utilizing gel and adhesive matrices and “membrane control” were included in these investigations. Each subject received at least two different formulations on 2 different days. The delivery systems were left in place for 24 hr, after which they were removed and subsequently analyzed for residual nitroglycerin content. The apparent dose for each subject was determined. This parameter is defined as the difference between the initial and final potencies of the transdermal systems after 24 hr of skin contact. The median apparent doses were 5.2, 9.4, 12.2, and 17.4 mg for theoretical doses of 5, 10, 15, and 20 mg, respectively. Although the data vary by as much as a factor of 10 between subjects, the plasma concentrations (from a smaller group of subjects) were shown to be proportional to surface area. Both apparent dose data and plasma concentration data for transdermal nitroglycerin show a significant level of variability. This is caused primarily by the inherent differences in human skin. Variability in plasma concentrations is nothing new to pharmacokinetics. Because of differences in clearance and volume of distribution, most drugs, given at the same dose, will show variable steady-state plasma concentrations. As long as the dose of drug is related to plasma concentrations, the physician can titrate a patient's dose. Transdermal drug application allows one to adjust dose by simply adjusting the active surface area of the transdermal delivery system.