Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers

Background: Oral transmucosal fentanyl citrate (OTFC) is a solid form of fe ntanyl that delivers the drug through the oral mucosa, The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain i s under evaluation. The aim of this study was to test the hypothesis that t he pharmacokinetics of OTFC do not change with multiple dosing. Methods: Twelve healthy adult volunteers received intravenous fentanyl (15 mu g/kg) or OTFC (three consecutive doses of 800 mu g) on separate study se ssions. Arterial blood samples mere collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maxim um concentration) were identified from the raw data and subjected to a nonp arametric analysis of variance. Population pharmacokinetic models for all s ubjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. Results: The shapes of the profiles of plasma concentration versus time for each dose of OTEC were grossly similar, No change was noted for maximum co ncentration or time to maximum concentration over the three doses, while mi nimum concentration did show a significantly increasing trend. Terminal hal f-lives for intravenous fentanyl and OTFC were similar. A two-compartment p opulation pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models d emonstrated rapid and substantial absorption of OTFC that did not change sy stematically with time and multiple dosing. Conclusions: The pharmacokinetics of OTFC were similar among subjects and d id not change with multiple dosing. Multiple OTFC dosing regimens within th e dosage schedule examined in this study can thus be formulated without con cern about nonlinear accumulation.