William Tracewell

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 μg (transmucosal), FBT 800 μg (oral), OTFC 800 μg (transmucosal), and fentanyl 400 μg (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 tmax 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 Cmax. 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.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated.Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products.After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1–2 mg/L at 3–4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC∞) of 18 mg • h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the ‘flip-flop’ phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The ‘true’ apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life.Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with Cssmax of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages.Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide, Cmax is less than proportional to dose, and tmax is prolonged with increasing dose.Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function.

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

AbstractBackground 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 200μg 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 (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve from time zero to 8 hours (AUC8), and AUC from time zero to the median tmax (AUCtmax′). 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 Cmax 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 tmax was not significantly different in the two groups: median tmax 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 AUCtmax′ values were 0.17ng · 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 AUC8 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 200μg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

Bioequivalence Following Buccal and Sublingual Placement of Fentanyl Buccal Tablet 400 μg 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-μg 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 μg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC∞), 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 Cmax and AUC∞ for the two sites of tablet placement: sublingual/buccal ratio for Cmax = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC∞ = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to tmax′ (AUCtmax′), where tmax′ is the median time to Cmax of a single 400-μg 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 Cmax (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.

Thalidomide Dose Proportionality Assessment following Single Doses to Healthy Subjects

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single‐dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgenes commercial Thalomid® thalidomide formulation in an open‐label, single‐dose, three‐way crossover study. Fifteen healthy subjects were given 50,200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dosenormalized Cmax and AUC0‐∞. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0‐∞ increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip‐flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomides low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.

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.

Single- and Multiple-dose Pharmacokinetics of a Hydrocodone Bitartrate Extended-release Tablet Formulated With Abuse-deterrence Technology in Healthy, Naltrexone-blocked Volunteers

PURPOSE A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse-deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against dose dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-dose administration in healthy, naltrexone-blocked subjects. METHODS In the single-dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-dose period of study 1, subjects received one 45-mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5-10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose in the single-dose period and after the final dose in the multiple-dose period. PK measures included maximum observed plasma drug concentration (C(max)), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC(0-t)), time to C(max) (T(max)), observed accumulation ratio (R(obs)), and steady-state plasma concentration (C(ss)). Safety and tolerability were assessed. FINDINGS The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-dose administration of hydrocodone ER 45 mg (study 1) were dose-normalized to 90 mg and pooled with data from study 2. As expected, C(max) was higher (125.4 vs 57.2 ng/mL), AUC(0-t) was higher (2561 vs 1095 ng·h/mL), and T(max) occurred earlier (5.0 vs 8.0 hours) with multiple-dose administration. Mean R(obs) after multiple-dose administration of hydrocodone ER was also slightly higher than predicted from single-dose data (2.8 vs 2.4). C(ss) were achieved within 5 days of twice-daily administration of both doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-dose (33%) and multiple-dose (29%) periods in study 1 and slightly higher in the multiple-dose (76%) than in the single-dose (53%) period in study 2. IMPLICATIONS The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-dose administration. The steady-state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings.

Dose Proportionality of Fentanyl Buccal Tablet in Doses Ranging from 600 to 1300μg in Healthy Adult Subjects

AbstractBackground: 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. Objective: The objective of this study was to assess the dose proportionality of FBT over a range of 600–1300 μg in healthy subjects. Methods: 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 μg). 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 (Cmax) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞), 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 Cmax versus dose and AUC∞ 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. Results: The slope for Cmax versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC∞ versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for Cmax and AUC∞ were within the predefined range of 0.711–1.289, dose proportionality was concluded over the 600–1300 μg range. The mean dose-normalized plasma fentanyl concentration reached 80% of Cmax 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. Conclusion: The dose proportionality of FBT from 600–1300 μg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 μg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 μg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Effects of Renal Impairment and Hepatic Impairment on the Pharmacokinetics of Hydrocodone After Administration of a Hydrocodone Extended‐Release Tablet Formulated With Abuse‐Deterrence Technology

Two open‐label, single‐dose, parallel‐group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended‐release (ER) formulation developed with the CIMA Abuse‐Deterrence Technology platform. Forty‐eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. Mean maximum observed plasma hydrocodone concentration (Cmax) in subjects with normal renal function, mild, moderate, and severe impairment, and end‐stage renal disease was 28.6, 33.4, 42.4, 36.5, and 31.6 ng/mL, and mean area under the plasma hydrocodone concentration‐versus‐time curve from time 0 to infinity (AUC0–∞) was 565, 660, 973, 983, and 638 ng·h/mL, respectively. Incidence of adverse events was 57%, 38%, 44%, 33%, and 56%, respectively. Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0–∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER.