Efficacy and tolerability of buccal buprenorphine in opioid-experienced patients with moderate to severe chronic low back pain: results of a phase 3, enriched enrollment, randomized withdrawal study.

A buccal film of buprenorphine (BBUP) was evaluated for safety and efficacy in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal study in opioid-experienced patients (30 to ≤160 mg/d morphine sulfate equivalent) with moderate to severe chronic low back pain taking around-the-clock opioid analgesics. Patients' opioid doses were tapered to ≤30 mg morphine sulfate equivalent before open-label titration with BBUP (range, 150-900 µg every 12 hours). Patients who responded (received adequate analgesia that was generally well tolerated for 14 days) were randomized to receive buprenorphine (n = 254) or placebo (n = 257) buccal film. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in mean average daily pain-intensity scores using a rating scale of 0 (no pain) to 10 (worst pain imaginable). In the intent-to-treat population, mean pain scores were 6.7 after opioid taper and declined to 2.8 after the BBUP titration period. After randomization, mean pain scores were lower in the BBUP group than in the placebo group; the difference between groups in the mean change from baseline to week 12 was -0.98 (95% CI, -1.32 to -0.64; P < 0.001). A significantly larger percentage of patients receiving BBUP than placebo had pain reductions ≥30% and ≥50% (P < 0.001 for both). In the double-blind portion of the study, the only adverse event reported more frequently with BBUP than placebo and in ≥5% of patients was vomiting (5.5% vs 2.3%). These findings demonstrate the efficacy and tolerability of BBUP in opioid-experienced patients taking around-the-clock opioid treatment for chronic low back pain.

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.

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.

Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers.

PURPOSE: Buprenorphine, a partial µ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. METHODS: Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 µg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-µg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 µg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. FINDINGS: In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 µg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers. IMPLICATIONS: The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.

Differentiating the Effect of an Opioid Agonist on Cardiac Repolarization From µ-Receptor-mediated, Indirect Effects on the QT Interval: A Randomized, 3-way Crossover Study in Healthy Subjects.

PURPOSE: A thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects. METHODS: Healthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia's formula (QTcF), and change-from-predose baseline QTcF (∆QTcF) was analyzed by using a mixed effect model. FINDINGS: Fifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ∆QTcF reaching 5.8 msec at 8 hours' postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ∆QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ∆QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval. IMPLICATIONS: The present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern.

Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain.

OBJECTIVES: Buprenorphine HCl buccal film has been developed for treating chronic pain utilizing BioErodible MucoAdhesive (BEMA(®)) delivery technology. Buccal buprenorphine (BBUP; Belbuca(TM), Endo Pharmaceuticals) was evaluated for the management of moderate to severe chronic low back pain (CLBP) requiring around-the-clock analgesia in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal study in opioid-naive patients. METHODS: Patients (n = 749) were titrated to a dose of BBUP (range, 150-450 µg every 12 h) that was generally well tolerated and provided adequate analgesia for ≥14 days, and then randomized to BBUP (n = 229) or placebo (n = 232), respectively. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in the mean of daily average pain intensity scores (numeric rating scale from 0 [no pain] to 10 [worst pain imaginable]). RESULTS: Patients were experiencing moderate to severe pain at study entry: mean (SD) = 7.15 (1.05). Following titration, pain was reduced to the mild range; 2.81 (1.07). After randomization, mean (SD) pain scores increased from baseline to week 12 more with placebo (1.59 [2.04]) versus BBUP: (0.94 [1.85]) with a significant between-group difference (-0.67 [95% CI: -1.07 to -0.26]; p = 0.0012). A significantly larger percentage of patients receiving BBUP versus placebo had ≥30% pain reduction (63% vs 47%; p = 0.0012). During double-blind treatment, the most frequent adverse events (AEs) with BBUP were nausea (10%), constipation (4%) and vomiting (4%). The most common AEs with placebo were nausea (7%), upper respiratory tract infection (4%), headache (3%) and diarrhea (3%). CONCLUSIONS: These findings demonstrate the efficacy and tolerability of BBUP among opioid-naive patients requiring around-the-clock opioid treatment for CLBP.

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.

Dose Proportionality and Pharmacokinetics of Fentanyl Buccal Soluble Film in Healthy Subjects : A Phase I, Open-Label, Three-Period, Crossover Study.

BACKGROUND 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.

Dose proportionality and pharmacokinetics of fentanyl buccal soluble film in healthy subjects: a phase I, open-label, three-period, crossover study.

BACKGROUND 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 [C(max)], area under the plasma concentration-time curve [AUC] from time zero to time of the last measurable concentration [AUC(last)], 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 C(max) values increased in a linear manner with values ranging from 0.383 ng/mL to 2.19 ng/mL, respectively. Mean AUC(last) values increased from 3.001 ng·h/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.

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 microg) administered by intravenous infusion, injectable fentanyl citrate (800 microg/16 mL) administered orally, and fentanyl buccal soluble film (800 microg) administered as a single film and as four separate 200 microg 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-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg 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 C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) 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.

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

BACKGROUND 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 pharmacokinetics 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 microg 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 [AUCinfinity]) 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(infinity) value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03 ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUCinfinity 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.

Bioavailability and metabolism of prochlorperazine administered via the buccal and oral delivery route.

Prochlorperazine has been accepted as an effective antiemetic for more than 50 years; however, its therapeutic success has been limited by its low and variable absorption and high first-pass metabolism. A buccal dosage form of prochlorperazine has been developed. This article discusses 2 clinical studies conducted to characterize the single-dose and multiple-dose pharmacokinetics of prochlorperazine and its metabolites after buccal administration. The results of these studies demonstrate that buccal administration of prochlorperazine produces plasma concentrations more than twice as high as an oral tablet, with less than half the variability. In addition to the metabolites, N-desmethyl prochlorperazine and prochlorperazine sulfoxide, 2 new metabolites, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, were identified and quantitated. Exposure to metabolites after the buccal prochlorperazine formulation was approximately half that observed after the oral tablet. Buccal administration of prochlorperazine, twice daily, should enhance the therapeutic role of prochlorperazine in preventing and treating nausea and vomiting.