Systemic exposure to armodafinil and its tolerability in healthy elderly versus young men: an open-label, multiple-dose, parallel-group study.

BACKGROUND: Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder. OBJECTIVE: This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R-modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects. METHODS: The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged ≥65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(τ)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed. RESULTS: All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(τ) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(τ) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age ≥75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(τ) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events. CONCLUSIONS: Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged ≥75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly.

Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study.

BACKGROUND: Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep apnea (OSA). The R-isomer of racemic modafinil has a half-life of approximately15 hours; the S-isomer has a half-life of 4 to 5 hours. The R-and S-isomers are equipotent, producing equivalent pharmacologic activity at equal concentrations. OBJECTIVE: The aim of this work was to compare the pharmacokinetic profiles of armodafinil (R-modafinil) and modafinil (racemic mixture with equal quantities of R- and S-isomers) at equal doses in patients with residual excessive sleepiness associated with continuous positive airway pressure-treated OSA. METHODS: This open-label study was conducted at 5 US centers from July 2008 to March 2009. Patients were randomized to 1 of 2 crossover administration sequences, ABCD or BADC, where A was a single armodafinil 200-mg dose, B was a single modafinil 200-mg dose, C was multiple daily modafinil 200-mg doses, and D was multiple daily armodafinil 200-mg doses. During multiple-dose administration, patients received 100 mg once daily for days 1 and 2, and 200 mg once daily for days 3 through 10. The pharmacokinetic parameters of principal interest for assessing the bioequivalence of armodafinil and modafinil were maximum concentration at 7 to 11 hours after dosing and the concentration-versus-time curve for this period. Analysis was performed via achiral high-performance liquid chromatography with ultraviolet detection using blood samples obtained over 72 hours after single-dose administration and over 24 hours after the multiple-dose regimen. For post hoc evaluation of bioequivalence, 90% CI values were also constructed for the geometric mean ratios of armodafinil to modafinil. Tolerability was assessed by the reported adverse events, clinical laboratory testing, vital sign measurements, ECGs, and physical exams. RESULTS: The study population was 83.3% male (35/42) and 76.2% white (32/42) with a mean (SD) age of 47.0 (8.30) years and a weight range of 66.3 to 127.4 kg. Plasma drug concentration-versus-time curves suggested comparable terminal half-lives (mean [SD] values were 16.5 [4.44] and 14.4 [3.22] hours for armodafinil and modafinil, respectively) but higher systemic exposure with armodafinil than modafinil (mean [SD] AUC(0-∞) values were 108.8 [31.66] and 66.4 [20.06] microg · h/mL for armodafinil and modafinil, respectively), as indicated by the high geometric mean ratios for the AUC (the AUC(0-∞)) ratio after a single dose was 1.64 [95% CI, 1.60-1.68; P < 0.001], and the AUC(0-τ) ratio after multiple doses was 1.69 [95% CI, 1.65-1.72; P < 0.001]) and, to a lesser extent, the ratio of the maximum plasma drug concentration after multiple doses (C(max) ratio = 1.37 [95% CI, 1.33-1.41; P < 0.001]). In addition, the ratios and associated 90% CIs for Cmax (137 [1.341.40]) and AUC(0-τ) (169 [1.66-1.75]) after multiple-dose administration did not meet the US Food and Drug Administration (FDA) criteria for bioequivalence (ie, ratio of geometric means between 80% and 125%). Reported adverse events were mild to moderate in intensity. The most frequently reported adverse events while receiving armodafinil or modafinil were headache (29% and 2%, respectively), diarrhea (12% and 5%), nausea (10% and 2%), and dizziness (10% and 5%). CONCLUSIONS: In this crossover study of patients with treated OSA, overall systemic exposure after armodafinil 200-mg administration was greater than that following modafinil 200-mg administration after both single and multiple doses. The pharmacokinetic profiles of the 2 drugs were notably different and did not meet the FDA criteria for bioequivalence.

Dose proportionality of fentanyl buccal tablet in doses ranging from 600 to 1300 microg in healthy adult subjects: a randomized, open-label, four-period, crossover, single-centre study.

Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving, and who are tolerant to, opioid therapy for underlying, persistent cancer pain. Breakthrough pain may be severe or excruciating, and some patients may require high doses of rapid-onset opioids to obtain adequate analgesia. The objective of this study was to assess the dose proportionality of FBT over a range of 600-1300 microg in healthy subjects. This was a randomized, open-label, four-period, crossover, single-centre study of FBT (Fentora) conducted in healthy adult subjects who were not tolerant to opioids. The study included 120 men and women aged 18-45 years with a body mass index of 20-30 kg/m2 who had no clinically significant findings on medical and psychiatric histories, physical examination, ECG or standard clinical laboratory tests, and who had a negative urine screen for drugs and alcohol. Eligible subjects were randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 microg). Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was administered to block the opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentration was measured through 72 hours after placement of FBT. The main outcome measures, maximum plasma fentanyl concentration (C(max)) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC(infinity)), were analysed to determine dose proportionality. Other pharmacokinetic parameters were also evaluated. Dose proportionality was concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the C(max) versus dose and AUC(infinity) versus dose curves were completely contained within the range of 0.711-1.289. The safety and tolerability of FBT were assessed throughout the study. The slope for C(max) versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC(infinity) versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for C(max) and AUC(infinity) were within the predefined range of 0.711-1.289, dose proportionality was concluded over the 600-1300 microg range. The mean dose-normalized plasma fentanyl concentration reached 80% of C(max) within 25 minutes; plasma fentanyl concentration was maintained at this level for 3 hours after dose. No unexpected safety or tolerability concerns were noted in the naltrexone-blocked healthy subjects. Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and headache. No serious AEs were reported. The dose proportionality of FBT from 600-1300 microg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 microg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 microg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.

Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects.

BACKGROUND AND OBJECTIVE: Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. METHODS: A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). RESULTS: Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil. CONCLUSIONS: At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies.

BACKGROUND AND OBJECTIVE: Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations. METHODS: Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50, 100, 200, 250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed. RESULTS: Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of approximately 13 hours, with similar mean maximum plasma drug concentration (C(max)) and median time to C(max) values. After reaching C(max), plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUC(last)) and AUC from time zero to infinity (AUC(infinity)) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis. CONCLUSIONS: Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.

Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies.

BACKGROUND AND OBJECTIVES: Armodafinil (R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects. METHODS: Pooled pharmacokinetic data from three separate randomized studies in 119 healthy subjects who received single or multiple (once daily for up to 14 days) oral doses of armodafinil ranging between 50 and 400 mg were analysed. The impact of food on the single-dose pharmacokinetic profile of armodafinil was also assessed in subjects following an overnight fast and after the consumption of a standard fatty meal. RESULTS: Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50-400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2-4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea. CONCLUSIONS: In the present analysis, armodafinil exhibited linear pharmacokinetics over the dose range of 50-400 mg. While food affected the rate but not the extent of absorption, peak plasma concentrations were reached in approximately 2 hours when the drug was taken on an empty stomach. With once-daily dosing, steady state appeared to be reached within 7 days. After reaching peak plasma levels, concentrations of armodafinil declined monophasically, with a mean elimination half-life of around 15 hours. Armodafinil was generally well tolerated.

Bioequivalence following buccal and sublingual placement of fentanyl buccal tablet 400 microg in healthy subjects.

BACKGROUND AND OBJECTIVE: The fentanyl buccal tablet (FBT) is formulated to enhance the rate and extent of fentanyl absorption across the buccal mucosa. FBT is indicated for the management of breakthrough pain (a transient flare of pain on a background of chronic pain otherwise controlled by treatment with opioids) in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. This study assessed the bioequivalence of a single 400-microg dose of FBT following buccal (i.e. above a molar tooth between the upper gum and cheek) and sublingual (i.e. placed under the tongue) placement in order to provide an alternative option to patients. METHODS: Healthy subjects were randomized to receive one FBT 400 microg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (C(max)) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC(infinity)), was established if the 90% confidence interval (CI) for the ratio of the means of sublingual/buccal values fell within the range of 0.80 to 1.25. RESULTS: Ninety subjects were enrolled (67 men, 23 women; median age 24 years), and 78 completed the study. The criteria for bioequivalence were met for both C(max) and AUC(infinity) for the two sites of tablet placement: sublingual/buccal ratio for C(max) = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC(infinity) = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to t(max') (AUC(tmax')), where t(max') is the median time to C(max) of a single 400-microg dose of FBT administered buccally (mean [SD]: 0.35 [0.16] ng . h/mL buccal; 0.35 [0.16] ng . h/mL sublingual) and for time to C(max) (median [range]: 0.75 [0.33-3.13] hours buccal; 0.78 [0.17-3.00] hours sublingual). FBT was generally well tolerated following placement at both sites in healthy volunteers administered naltrexone. CONCLUSION: The results of this study support sublingual FBT placement as a viable alternative to buccal placement in patients who may require an alternate administration site.

Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects.

BACKGROUND AND OBJECTIVE: Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. METHODS: Healthy men and nonpregnant women aged 18-45 years with a body mass index of

Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis: a pilot study.

BACKGROUND AND OBJECTIVES: Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) - an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients - in patients with or without oral mucositis. METHODS: In this open-label study, patients with or without oral mucositis self-administered a single 200 microg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the plasma concentration-time curve from time zero to 8 hours (AUC(8)), and AUC from time zero to the median t(max) (AUC(tmax)(')). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration. RESULTS: Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median C(max) values were comparable: 1.14 ng/mL (range 0.26-2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21-2.34 ng/mL) in patients without mucositis. The t(max) was not significantly different in the two groups: median t(max) was 25.0 min (range 15-45 min) in patients with mucositis and 22.5 min (range 10-121 min) in patients without mucositis. Median AUC(tmax') values were 0.17 ng . h/mL (range 0.04-0.52 ng . h/mL) in patients with mucositis, and 0.20 ng . h/mL (range 0.00-0.65 ng . h/mL) in patients without mucositis. The corresponding AUC(8) values were 2.05 ng . h/mL (range 1.16-3.83 ng . h/mL) and 1.55 ng . h/mL (range 0.74-3.07 ng . h/mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported. CONCLUSION: The absorption profile of a single dose of FBT 200 microg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate.

This study assessed the absolute and relative bioavailabilities and transmucosal and gastrointestinal absorbency of fentanyl buccal tablet (FBT) and oral transmucosal fentanyl citrate (OTFC). In a randomized crossover design, 26 healthy subjects received FBT 400 microg (transmucosal), FBT 800 microg (oral), OTFC 800 microg (transmucosal), and fentanyl 400 microg (intravenous). The transmucosal FBT had the highest absolute bioavailability (0.65) compared with the oral FBT (0.31) or transmucosal OTFC (0.47). More fentanyl was absorbed transmucosally from FBT than OTFC (48% vs 22%). Median t(max) values were shorter following the transmucosal FBT (47 minutes) than the oral FBT (90 minutes) or the transmucosal OTFC (91 minutes). Transmucosal administration of FBT compared with dose-normalized OTFC resulted in higher total systemic fentanyl exposure, higher early systemic exposure, and higher C(max). The rate and extent of fentanyl absorption were greater following administration of FBT compared to OTFC. An approximately 30% smaller dose of FBT achieved systemic exposures comparable to OTFC.

Single-dose and steady-state pharmacokinetics of fentanyl buccal tablet in healthy volunteers.

This study evaluated the single-dose and steady-state pharmacokinetics of fentanyl buccal tablet 400 microg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor-mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 microg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 microg on day 1 and the last dose of fentanyl buccal tablet 400 microg on day 9. Following single- and multiple-dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single-dose regimen and 1.77 ng/mL for the multiple-dose regimen. Steady state was reached within 5 days, consistent with the observed median half-life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single-dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple-dose administration.

Comparison of equivalent doses of fentanyl buccal tablets and arteriovenous differences in fentanyl pharmacokinetics.

BACKGROUND: The fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa. AIM: To evaluate the bioequivalence of microg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers. METHODS: Twenty-seven healthy adults, aged 19-45 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100 microg tablets simultaneously or one FBT 400 microg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400 microg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout. RESULTS: Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100 microg tablets simultaneously compared with one FBT 400 microg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study. CONCLUSION: Despite small differences in C(max) and AUC(infinity) (on average 12% and 13%, respectively), FBT administered as four 100 microg tablets simultaneously compared with one 400 microg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum concentrations observed with four 100 microg tablets. A substantially higher C(max) was reached earlier in the arterial than in the venous circulation.

Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1,080 pg versus oral transmucosal fentanyl citrate 1,600 pg and dose proportionality of FEBT 270 to 1,300 microg: a single-dose, randomized, open-label, three-period study in healthy adult volunteers.

BACKGROUND: The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain. OBJECTIVES: The primary objective of this study was to compare the relative bioavailability of FEBT 1,080 microg with that of oral transmucosal fentanyl citrate (OTFC) 1,600 microg, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1,300 microg in healthy adult volunteers. METHODS: This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1,080 microg followed by single-dose OTFC 1,600 microg, or vice versa; in period 3 (dose-proportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1,300 microg. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 microg, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For tolerability analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed. RESULTS: A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC(0-infinity))) was statistically similar between FEBT 1,080 microg and OTFC 1,600 microg (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng x h/mL). However, the mean (SD) C(max) with FEBT 1,080 microg was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1,600 microg (P = NS), and the T(max) of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC(0-Tmax'); ie, AUC from time 0 to 1 hour the median T(max) of the reference dose of FEBT [810 microg]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] ng x h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC(0-infinity) and AUC(0-Tmax') over the range of FEBT 270 to 1,300 microg. Increases in C(max) were less than dose proportional at FEBT doses >810 microg. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC. CONCLUSIONS: In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1,300 microg, whereas doses above 810 microg showed a less-than-dose-proportional increase in C(max). The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (C(max) and AUC(0-Tmax')) and significantly more rapidly (T(max)) with FEBT compared with OTFC.

Pharmacokinetic properties of fentanyl effervescent buccal tablets: a phase I, open-label, crossover study of single-dose 100, 200, 400, and 800 microg in healthy adult volunteers.

BACKGROUND: The fentanyl effervescent buccal tablet (FEBT) is designed to enhance the rate and extent of the absorption of fentanyl, an opioid, through the buccal mucosa. OBJECTIVES: The purposes of this study were to assess the dose proportionality of FEBT in healthy volunteers over the potential therapeutic dose range (100-800 microg) and characterize the pharmacokinetic (PK) profile of 4 doses (100, 200, 400, and 800 microg) of FEBT. METHODS: This Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii. Healthy adult volunteers with intolerance to opioids were randomly assigned to receive 1 of 4 single-dose sequences of FEBT: 100, 200, 400, and 800 microg (selected to encompass the anticipated therapeutic dose range), with each successive administration separated by a washout period of >or=7 days. Naltrexone hydrochloride (50-mg tablet) was administered-15 and 3 hours before and 9 hours after FEBT administration to block opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentrations were measured from venous samples obtained over 72 hours after FEBT administration. Early fentanyl exposure was assessed using AUC from time 0 to 0.75 hour (the median T(max) of the reference dose [100 microg]) (AUC(0-Tmax')). Adverse events (AEs) were monitored and recorded throughout the study by medically qualified personnel. RESULTS: Thirty-two subjects (26 men, 6 women; mean [SD] age, 29.3 [7.2] years [range, 19-44 years]; mean [SD] weight, 74.7 [10.7] kg) were enrolled. Median T was between 35 and 45 minutes after FEBT administration. AUC(0-infinity) and C(max) increased approximately linearly with increasing doses of FEBT. Mean plasma fentanyl concentrations decreased from C(max) in a biexponential manner at the 100- and 200-microg doses and decreased in a triexponential manner at the 800-mug dose. Despite the triexponential decrease in the mean profile observed with the 400-microg dose, a biexponential decrease was observed in approximately half of the individual profiles. AUC(0-Tmax') ranged from 0.09 ng x h/mL with the 100-microg dose to 0.52 ng x h/mL with the 800-microg dose. The most commonly reported AEs in the 100-, 200-, 400-, and 800-microg dose groups were as follows: application-site erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subjects; and headache, 3, 2, 1, and 4 subjects. None of the AEs were serious. CONCLUSIONS: In this study of the dose proportionality of FEBT in healthy volunteers, the PK profile of FEBT was characterized by a high early systemic exposure of fentanyl (0.09-0.52 ng x h/mL). Dose-dependent parameters (C(max) and AUC) increased in an approximately dose-proportional manner from 100 to 800 microg FEBT.

Pharmacokinetics and dose proportionality of fentanyl effervescent buccal tablets in healthy volunteers.

BACKGROUND AND OBJECTIVES: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This study was undertaken to characterise the pharmacokinetics and assess the dose proportionality of FEBT in healthy volunteers within the potential therapeutic dose range. METHODS: Twenty-five healthy adults (mean age 33 years) completed a single-dose, randomised, open-label, four-dose, four-period, crossover study of FEBT. They were administered FEBT 200, 500, 810 or 1080microg. The subjects in this study were not opioid tolerant; therefore, naltrexone was administered to block any opioid receptor-mediated effects of fentanyl. Venous blood samples for measurement of serum fentanyl concentrations were obtained over 36 hours following dosing. Adverse events were recorded throughout the study. RESULTS: The pharmacokinetics of FEBT were characterised by an absorption phase with a median time to reach maximum serum concentration (tmax) of 0.75-0.99 hours that was consistent irrespective of dose. Mean serum fentanyl concentrations exhibited a biexponential decline from peak after FEBT 200 and 500microg doses and a triexponential decline after FEBT 810 and 1080microg doses. The maximum serum concentration (Cmax) of fentanyl was proportional up to and including the 810microg dose. The increase in Cmax was 20% less than proportional at the 1080microg dose. Systemic exposure to fentanyl, as measured by the area under the serum concentration-time curve from time zero to infinity (AUCinfinity), increased proportionally with increasing doses of FEBT (200-1080microg). No serious adverse events were reported during the study. CONCLUSION: The pharmacokinetics of FEBT were characterised by a high early fentanyl concentration as a result of absorption across the buccal mucosa of the oral cavity, which results in bypassing first-pass metabolism. This high early tmax contributed to enhanced early systemic fentanyl exposure. Maximum concentration and AUCinfinity of FEBT increased in a dose-proportional manner from 200 to 810microg. This study provides preliminary pharmacokinetic data for FEBT across the potential therapeutic dose range.