Niraj Vasisht

Formulation selection and pharmacokinetic comparison of fentanyl buccal soluble film with oral transmucosal fentanyl citrate: a randomized, open-label, single-dose, crossover study.

AbstractBackground and Objectives: BioErodible MucoAdhesive (BEMA®) is a new transmucosal drug delivery system designed to improve and ease the administration of drugs by this route. The first product that uses this novel delivery system contains fentanyl and is intended for the treatment of breakthrough pain in opioid-tolerant patients with cancer. The generic name is fentanyl buccal soluble film (FBSF). The objectives of this study were to compare the pharmacokinetic profile of FBSF formulations at three different pHs (pH 6, pH 7.25 and pH 8.5) and to understand the differences in the pharmaco-kinetics of fentanyl from FBSF compared with that of oral transmucosal fentanyl citrate (OTFC). Methods: This was a randomized, open-label, single-dose, four-period, Latin-square crossover study consisting of a 9-day inpatient treatment period. The study was conducted at a phase 1 clinical research unit in Austin, TX, USA. Twelve healthy subjects were enrolled, nine males and three females, between the ages of 21 and 44 years. Each subject received four 800 µg doses of fentanyl: single doses of the three FBSF formulations (pH 6, pH 7.25 and pH 8.5) and OTFC, with concurrent naltrexone. Plasma fentanyl concentrations were measured over a 48-hour period after each study dose. Pharmacokinetic parameters were calculated and compared. Results: Peak plasma fentanyl concentrations (Cmax) and overall fentanyl systemic exposure (area under the plasma concentration-time curve from time zero extrapolated to infinity [AUC∞]) for each of the three FBSF formulations were greater than for OTFC. The pH 7.25 FBSF formulation provided the earliest time to reach Cmax (tmax), the highest Cmax value and the greatest AUC∞ value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUC∞ 14.5 vs 10.3 ng · h/mL). Conclusions: All three FBSF formulations produced greater peak plasma concentrations and overall exposure to fentanyl than OTFC. In particular, the pH 7.25 FBSF formulation showed the most favourable pharmacokinetic profile of the three FBSF formulations. In comparison with OTFC, the pH 7.25 FBSF formulation produced the fastest and most efficient fentanyl delivery and was selected for further clinical development.

Single‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film

Objective The objectives of the study were to determine the absolute bioavailability of fentanyl from fentanyl buccal soluble film, estimate the percentage of a fentanyl dose absorbed through the buccal mucosa, and compare the bioavailability of equivalent doses administered either as single or multiple dose units. Design Open-label, randomized, four-period, Latin-square crossover pharmacokinetic study. Setting Inpatient phase 1 unit. Patients Twelve healthy volunteers. Interventions Injectable fentanyl citrate (200 µg) administered by intravenous infusion, injectable fentanyl citrate (800 µg/16 mL) administered orally, and fentanyl buccal soluble film (800 µg) administered as a single film and as four separate 200 µg films simultaneously. Outcome Measures Plasma concentrations after fentanyl dosing; pharmacokinetic parameters. Results The two buccal film treatments were bioequivalent and both had an absolute bioavailability of 71%. The percentage of an administered dose absorbed through the buccal mucosa was calculated to be 51%. Conclusions Fentanyl buccal soluble film effectively delivers a high percentage of the administered fentanyl dose and nearly identical plasma profiles are obtained when equivalent doses are delivered by single or multiple dosage units.

Evaluation of the Single‐ and Multiple‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film in Normal Healthy Volunteers

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid‐tolerant patients with cancer. This open‐label, 3‐period, sequential dose study evaluated the dose‐to‐dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600‐or 1800‐μg doses of FBSF in 12 naltrexone‐blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 μg of FBSF on day 1 and day 4 and three 600‐μg doses administered at 1‐hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48‐hour period after each single dose of FBSF and 72 hours after the 3‐dose regimen. Peak plasma concentrations (mean Cmax = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC0–12 = 6.3 and 6.2 h·ng/mL; mean AUCinf = 9.14 and 9.60 h·ng/mL) were nearly identical after the 2 single doses (P≥ .1, all comparisons). Cmax and overall fentanyl exposure (AUCinf) increased approximately 3‐fold with the 3‐dose regimen compared with the single‐dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

Dose Proportionality and Pharmacokinetics of Fentanyl Buccal Soluble Film in Healthy Subjects

AbstractBackground and Objectives: Fentanyl buccal soluble film (FBSF) is a small, bilayered, water-soluble polymer film (BioErodible MucoAdhesive; BEMA™) that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. It is approved for the treatment of cancer breakthrough pain in adult opioid-tolerant patients. The objective of this study was to evaluate the dose proportionality of the pharmacokinetics of FBSF in healthy subjects across a range of doses. Methods: This was a phase I, open-label, single-dose, three-period, Latin-square crossover study in which 12 healthy subjects received single FBSF doses of 200, 600 and 1200 μg with 72 hours between doses. Oral naltrexone was administered to each subject prior to and after each study dose. Serial venous blood samples were collected for 48 hours after study drug administration. Adverse events were recorded throughout the study. Dose linearity was examined using a power model (P=a×Doseb), where P represents the dependent variable (maximum plasma drug concentration [Cmax], area under the plasma concentration-time curve [AUC] from time zero to time of the last measurable concentration [AUClast], or AUC from time zero to infinity [AUC∞]), and a and b are constants. A value of b ≈ 1 indicated linearity. Results: Following administration of FBSF doses of 200–1200 μg, mean Cmax values increased in a linear manner with values ranging from 0.383 ng/mL to 2.19ng/mL, respectively. Mean AUClast values increased from 3.001 ng ·/mL to 19.17 ng·h/mL and mean AUC∞ increased in a linear manner from 3.456 ng·h/mL to 20.43 ng ·h/mL. All reported adverse events were considered to be mild to moderate in severity. Conclusions: This study demonstrates that peak fentanyl plasma concentrations and overall exposure increase in a dose-proportional manner following administration of FBSF.

Poster 23: Fentanyl Buccal Soluble Film (FBSF) Offers High Absolute Bioavailability and Demonstrates Faster Absorption and Greater Exposure to Fentanyl Compared to Oral Transmucosal Fentanyl Citrate (OTFC)

ously determined FBSF dose (6 episodes) or placebo (3 episodes). Main Outcome Measures: In FEN-110, plasma fentanyl concentrations were measured at various time points. In FEN-201, efficacy was measured by the sum of pain intensity difference (SPID), and safety was evaluated on the basis of reported adverse events. Results: Mean peak plasma fentanyl concentrations and systemic fentanyl exposure increased in a linear and doseproportionate manner with FBSF dose (P .0001). For the 80 patients in the FEN-201 study, mean SPID values for FBSF treated episodes were statistically significantly greater than placebo starting at 15 minutes (P .05) and were maintained through 60 minutes. The most common treatment-related adverse events were somnolence (6.0%), nausea (5.3%), dizziness (4.6%), and vomiting (4.0%). There were no treatment-related adverse events at the application site. Conclusions: There is a linear and dose proportionate increase in fentanyl plasma concentrations across the FBSF dose range. FBSF provides patients with an effective means to control cancer BTP with a favorable tolerability profile.

Poster 22: Fentanyl Buccal Soluble Film (FBSF) Demonstrates Dose-Proportional Fentanyl Exposure and Favorable Efficacy and Tolerability in the Management of Breakthrough Pain in Opioid Tolerant Cancer Patients

been evaluated by her internist, neuro-ophthalmologist, otolaryngologist and another pain physician. Previous work-up included computed tomography (CT) of the chest done in December 2007 and magnetic resonance imaging (MRI) of her brain in May 2008, which were both negative. She was diagnosed with trigeminal neuralgia and optic migraines and was started on gabapentin. On presentation to the rehabilitation clinic in December 2008, she complained of ongoing right facial pain and headache in addition to non-radiating low back pain. A thorough history and examination revealed normal reflexes, strength and hip range of motion. Straight leg raising test was negative and lumbar tenderness was not assessed per the patient’s request. There was right-sided ptosis, tenderness over the right temporal artery and fullness of the right eyelid with eye erythema, facial flushing, but no miosis. Blood work, MRI of the lumbo-sacral (L-S) spine and a CT scan of the chest were ordered. Setting: Outpatient rehabilitation clinic. Results: Blood work was normal. MRI of the L-S spine showed a lesion in the left sacrum suspicious for metastasis in addition to severe stenosis. CT of the chest revealed a new right hilar mass suspicious for metastasis and several noncalcified nodular densities in the lungs bilaterally. Discussion: We propose that this patient had a Pancoast tumor on the right that was compressing the sympathetic chain thus causing her symptomatology. She was referred back to her internist and oncologist for further work-up. Conclusions: The most common factor producing the preganglionic Horner’s syndrome is malignant tumors. It is important to keep this diagnosis in mind when evaluating a patient with a history of cancer who presents with headaches and facial pain.