Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain

Abstract

AimsIt is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. MethodsEleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 m g, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS). Pharmacokinetic parameters were calculated by noncompar tment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. ResultsThe data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 m g) for dose adjusted AUC ( F = 0.42, P = 0.6660), dose adjusted C max ( F = 0.08, P = 0.9206) and Tmax ( F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100 m g) in dose adjusted AUC from the three-period crossover analysis was -0.016 min·ng/ ml ( t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t max increased from 39.7 ± 17.4 to 48.7 ± 26.3 and 56.7 ± 24.6 min for the 100, 200 and 400 m g doses, respectively. Adverse events were few and did not increase with increasing dose.B. Lennernäs et al. 25059 :2 Br J Clin Pharmacol ConclusionWith this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

The use of sublingual fentanyl for breakthrough pain by using doses proportional to opioid basal regimen

“…This finding confirms pharmacokinetics studies in which a detectable plasma concentration of fentanyl occurred in 8-11 minutes 21 . A reduction of approximately two points or a reduction of approximately 30% of pain intensity has been reported to be a cut-off for clinically important difference 29 .…”

“…Sublingual fentanyl (SLF) is a second generation ROO, formulated as a rapidly disintegrating tablet system containing a mixture of carrier particles coated with active drug particles and containing a mucoadhesive agent. The bioavailability of SLF is estimated to be about 70% 20 , with an interindividual variability lower than that reported with oral transmucosal fentanyl 21 . Controlled studies have demonstrated the efficacy and safety of SLF for the management of BTP 22,23 .…”

Assessment and management of breakthrough pain in cancer patients: Current approaches and emerging research

“…However, further work with this approach is needed before widespread use. Other studies involving sublingual sufentanil and fentanyl [36][37][38] also suggest a very rapid onset of these lipid-soluble opioids.…”

Fentanyl for the Treatment of Tumor-Related Breakthrough Pain

“…With fentanyl sublingual tablets (FST), the first trace of fentanyl in the blood can be demonstrated 8 to 10 minutes after administration; the maximum concentration is seen in a dose-dependent manner after 40 to 58 minutes (16). The bioavailability has not yet been investigated in studies; it is estimated at 70% (17).…”