A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches

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Abstract

We compared the pharmacokinetic profiles of the highest marketed doses of three different patch systems using a crossover study design. Specifically, each of the 25 subjects was assigned to receive the Pharmacia-Upjohn (McNeil) 15-mg, 16-h patch, the Novartis 21-mg, 24-h patch, and the Alza (SmithKline Beecham) 21-mg, 24-h patch. Subjects used each patch for 3 consecutive days, applying a new patch each morning. Plasma nicotine concentrations were measured 15 times during the first 24-h period and at 48, 48.5, 49.5, and 51 h following initial patch application. Measures of total nicotine absorbed (AUC), maximum plasma nicotine concentration (Cmax) and minimum plasma nicotine concentration (Cmin), were higher for the 21-mg, 24-h patches than for the 15-mg, 16-h patch during both the first day of dosing and during the modeled steady-state period (48–72 h after initial application). Within the 21-mg, 24-h patch systems, the Alza patch produced significantly higher AUC and Cmax values during acute dosing and during steady state, but there was no difference between Cmin values. The time to reach Cmax (Tmax) was fastest for the Alza patch system; the Pharmacia-Upjohn patch produced a faster Tmax than the Novartis patch. These results indicate that there are significant differences between the pharmacokinetics of the currently marketed patch systems, which may be important for effective relief of withdrawal symptoms and cigarette craving.

Introduction

Several forms of nicotine replacement therapy produce overall similar beneficial results of approximately twofold increases in cessation rate compared to persons receiving placebo [9]. Nonetheless, it is plausible that differences in the amount and pattern of nicotine delivery from patches may confer clinical advantages and disadvantages to individual patch users as cigarette users also vary in the amount and pattern of nicotine obtained from smoking. For example, heavily dependent smokers reliably smoke immediately upon awakening in the morning and attain higher overall nicotine blood levels during the day [5]. Furthermore, the effects of nicotine vary as a function of the speed and amount of nicotine administered. For example, at the extreme condition of the cigarette, small amounts of nicotine are very rapidly absorbed, producing a cascade of electrophysiologic, cardiovascular, and neurohormonal effects [8], [14]. Similarly, across three brands of oral snuff with similar nicotine content, but varying pH, the peak plasma nicotine concentrations, and several behavioral effects were directly related to the pH, and, hence, speed of nicotine absorption [6]

Several reviews have reported on the pharmacokinetics of the four patch systems [1], [4], [7], [8], [10]. These reviews report differences between the systems in terms of both amount of nicotine delivered, as well as rate of delivery; however, the data reported were taken from studies of individual systems. Because these studies used different subject groups and protocols, inferences about the differences between the systems is limited. The current study compared the pharmacokinetic profiles of currently marketed patch systems, using a double-blind, incomplete block study design. The three patch systems studied are manufactured by Pharmacia-Upjohn, Novartis, and Alza. Although other patch systems have been marketed, we selected these three on the basis that they appeared to be the three primary patch types of global utilization and appeared to represent diverse patch types.

Section snippets

Subjects

An Institutional Review Board approved the study, and all subjects provided written informed consent. Of the 25 subjects (nine females) who completed the study, two were Asians, two were blacks, 20 were whites, and one was Hispanic. The mean age of the subjects was 25.8 years (S.D.=7.3) and the mean weight was 73.3 kg (S.D.=12.5)

Inclusion criteria consisted of the following: smokers who smoked at least 10 cigarettes per day and had a plasma cotinine level of at least 100 ng/ml at baseline;

Results

Fig. 1 shows the plasma nicotine concentrations measured during the first 24 h of patch exposure and the steady-state modeled nicotine plasma concentrations over the subsequent 2 days of exposure. Table 1 shows the actual measured pharmacokinetic parameters calculated for the first day of patch administration (0–24 h). Table 2 shows the pharmacokinetic parameters calculated from modeled data during the second and third days of patch administration (48–72 h).

As shown in Table 1, Table 2, the

Discussion

The results of this study demonstrated significant differences in nicotine delivery among transdermal patches at the highest marketed dose and approved duration of use (i.e., 16 or 24 h). This is consistent with reviews [1], [4], [7], [8], [10] that have been reported on the pharmacokinetics of the four patch systems from studies of individual systems. The data showed that the 21-mg, 24-h patches delivered a higher relative dose of nicotine over the course of the day than the 15-mg, 16-h patch,

Acknowledgements

This research was funded by SmithKline Beecham Consumer Healthcare.

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