Andrew Finn

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.

Absorption and tolerability of fentanyl buccal soluble film (FBSF) in patients with cancer in the presence of oral mucositis

Purpose Fentanyl buccal soluble film (FBSF) consists of a small, bilayered, water-soluble polymer film that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. The purpose of this study was to evaluate the absorption of fentanyl from FBSF in patients with cancer, with and without grade 1 oral mucositis, and to assess the tolerability of FBSF in this patient population. Patients and methods In an open-label, single-dose study, two groups of opioid-naive patients (ie, not receiving opioids on a regular basis) with cancer received a 200 μg dose of FBSF. Patients in cohort I (n = 7) had grade 1 mucositis, and patients in cohort II (n = 7) were age- and gender-matched controls without mucositis. The FBSF dose was placed on the area of mucositis in cohort I and on a matching location in cohort II. Blood samples were collected up to 4 hours after administration, and safety assessments were made throughout the study. Results Peak plasma concentration and area under the concentration–time curve from time 0 to 4 hours post-dose values of patients in the grade 1 mucositis cohort were lower than those observed in patients without mucositis. There was no application site irritation reported in any patient, regardless of mucositis status. Mild somnolence was reported by two patients with mucositis. There were no deaths or serious adverse events reported in this study. Conclusion The results of this study indicate that application of FBSF to an area of grade 1 mucositis does not result in increased fentanyl exposure or irritation of the mucosa. The 200 μg dose of FBSF was well tolerated.

Intra- and interindividual variabilities in the pharmacokinetics of fentanyl buccal soluble film in healthy subjects: a cross-study analysis.

BACKGROUND AND OBJECTIVE Breakthrough pain describes transient exacerbations of pain that occur in cancer patients with adequately controlled background pain. Transmucosal fentanyl administration produces rapid-onset and short-duration analgesia that is effective for treating patients with breakthrough pain. Although a significant amount of research has been devoted to the study of speed of analgesia onset of transmucosal fentanyl products, few data exist on their variability in absorption, particularly within the same individual, despite the importance of this characteristic to the dose-to-dose reliability of their analgesic effect. This cross-study analysis aimed to evaluate the intra- and interindividual pharmacokinetic differences of fentanyl administered via fentanyl buccal soluble film in healthy subjects. METHODS Data were evaluated from 24 subjects in two pharmacokinetic studies of fentanyl administered via fentanyl buccal soluble film (Breakyl®/Onsolis™; BEMA® [BioErodible MucoAdhesive] technology). In one study, 12 healthy subjects received 600 μg doses of fentanyl as single film on two separate occasions; in the second study, 12 different healthy subjects received 800 μg doses of fentanyl on two separate occasions, one as a single 800 μg film and the other as four 200 μg films. RESULTS The analysis showed a minimal intraindividual variability and a relatively higher interindividual variability in pharmacokinetic parameters (i.e. maximum plasma concentration, area under the plasma concentration-time curve from time zero to infinity). The coefficient of variation for intraindividual exposure to fentanyl variability was 7-10%, and for interindividual variability was 23-39%. CONCLUSION The minimal intraindividual variability in fentanyl absorption from the buccal soluble film demonstrates a predictable dose-to-dose exposure, which is a very desirable attribute for a medicine that is intended to treat breakthrough cancer pain, suggesting that this product would be expected to produce consistent effects in clinical practice. The greater interindividual variability highlights the need for individual titration of this product (as occurs with similar transmucosal fentanyl products), and for the availability of an adequately wide dose range.

Intra- and Interindividual Variabilities in the Pharmacokinetics of Fentanyl Buccal Soluble Film in Healthy Subjects

AbstractBackground and Objective: Breakthrough pain describes transient exacerbations of pain that occur in cancer patients with adequately controlled background pain. Transmucosal fentanyl administration produces rapid-onset and short-duration analgesia that is effective for treating patients with breakthrough pain. Although a significant amount of research has been devoted to the study of speed of analgesia onset of transmucosal fentanyl products, few data exist on their variability in absorption, particularly within the same individual, despite the importance of this characteristic to the dose-to-dose reliability of their analgesic effect. This cross-study analysis aimed to evaluate the intra- and interindividual pharmacokinetic differences of fentanyl administered via fentanyl buccal soluble film in healthy subjects. Methods: Data were evaluated from 24 subjects in two pharmacokinetic studies of fentanyl administered via fentanyl buccal soluble film (Breakyl®/Onsolis™; BEMA® [BioErodible MucoAdhesive] technology). In one study, 12 healthy subjects received 600 µg doses of fentanyl as single film on two separate occasions; in the second study, 12 different healthy subjects received 800 µg doses of fentanyl on two separate occasions, one as a single 800 µg film and the other as four 200 µg films. Results: The analysis showed a minimal intraindividual variability and a relatively higher interindividual variability in pharmacokinetic parameters (i.e. maximum plasma concentration, area under the plasma concentration-time curve from time zero to infinity). The coefficient of variation for intraindividual exposure to fentanyl variability was 7–10%, and for interindividual variability was 23–39%. Conclusion: The minimal intraindividual variability in fentanyl absorption from the buccal soluble film demonstrates a predictable dose-to-dose exposure, which is a very desirable attribute for a medicine that is intended to treat breakthrough cancer pain, suggesting that this product would be expected to produce consistent effects in clinical practice. The greater interindividual variability highlights the need for individual titration of this product (as occurs with similar transmucosal fentanyl products), and for the availability of an adequately wide dose range.

Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine

Objective Assess whether patients with chronic pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full μ-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods. A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication. Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%). Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control.

Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals

Buprenorphine and buprenorphine–naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine–naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine–naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation.

Low-dose naloxone provides an abuse-deterrent effect to buprenorphine

In developmental research, plasma buprenorphine concentrations comparable to a 2 mg buprenorphine–naloxone (BN) sublingual tablet have been achieved with a 0.75 mg dose of BN buccal film, a small, bioerodible polymer film for application to mucosal membranes. This was a randomized, double-blind, placebo-controlled, single-dose, four-period crossover study in opioid-dependent subjects with chronic pain receiving >100 mg oral morphine equivalents daily who experienced withdrawal following a naloxone challenge dose. The objective of the study was to determine if intravenous (IV) naloxone doses of 0.1 and 0.2 mg would produce a withdrawal response when coadministered with a 0.75 mg IV dose of buprenorphine. Fifteen subjects receiving 90–1,260 mg oral morphine equivalents per day enrolled and completed the study. Precipitated withdrawal occurred in 13% (2/15) of placebo-treated subjects and 47% (7/15) of buprenorphine-treated subjects. When combined with the 0.75 mg dose of buprenorphine, a 0.1 mg dose of naloxone increased the incidence of precipitated withdrawal to 60%, and a 0.2 mg dose of naloxone increased the incidence to 73%. By 15 minutes postdose, the mean change in Clinical Opioid Withdrawal Scale (COWS) score from predose was 3.0 for placebo, 6.9 for buprenorphine, 9.8 for BN 0.1 mg, and 12.4 for BN 0.2 mg. The mean COWS score with each active treatment was significantly greater than placebo (P<0.001), and the mean COWS score for each of the naloxone-containing treatments was significantly greater than for buprenorphine alone (P<0.001). Naloxone doses as low as 0.1 mg added an abuse-deterrent effect to a 0.75 mg IV dose of buprenorphine.