The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS)

Introduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS. Methods: All three studies were single-centre, open-label, randomised, crossover studies. The fentanyl HCl PCTS was applied to the upper outer arm of all participants. In the first study, participants (n = 30) received three fentanyl HCl PCTS 25 mu g treatments: two sequential doses hourly for 23.33 hours, six sequential doses every 3 hours for 22 hours, and 72 doses continuously over 12 hours. Participants (n = 31) in the second study received three fentanyl HCl PCTS 40 mu g treatments: two sequential doses hourly over 23.33 hours, six sequential doses every 3 hours over approximately 10 hours, and 80 doses continuously over 13.33 hours. In the third Study, participants (n = 28) received four fentanyl HCl PCTS 40 mu g treatments: 6, 1 8 36 and 80 doses over 1, 3, 6 and 13.33 hours, respectively. Naltrexone was used to block the opioid effects of fentanyl. Pharmacokinetic parameters, including maximum serum fentanyl concentration (C-max), time to C-max (t(max)), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)) were determined. Results: In the first study, the dose-normalised AUC (AUC(n)) values for the 2- and 6-dose sequence treatments were not significantly different (p = 0.937), suggesting that the frequency of dosing has little effect on the amount of fentanyl absorbed; however, the AUC(n) for the 72-dose treatment was significantly lower than that of the other treatments (p = 0.001), which were of longer duration. The results of the second study paralleled those from the first, suggesting that the bioavailability of fentanyl delivered by the PCTS increases as a function of time and is likely to be independent of dosing frequency. Results from the third study suggested that approximately 40% of the nominal 40 mu g fentanyl dose is absorbed during the first hour of treatment, with the full nominal dose absorbed after approximately 10 hours. The fentanyl HCl PCTS was well tolerated. Conclusion: The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.