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PHARMACOKINETICS |
From Cephalon, Inc, Frazer, Pennsylvania.
Address for reprints: Address for correspondence: Mona Darwish, PhD, Cephalon, Inc, 41 Moores Road, Frazer, PA 19355; e-mail: mdarwish{at}cephalon.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: fentanyl buccal tablet • oral transmucosal fentanyl citrate • bioavailability
Fentanyl buccal tablet is formulated using a new drug delivery technology that produces an effervescent reaction that facilitates fentanyl absorption across the buccal mucosa, increasing early systemic exposure to the opioid.4-7 Fentanyl buccal tablet has been evaluated in clinical studies for the management of cancer-related breakthrough pain, a transient exacerbation or flare of pain that occurs on a background of otherwise controlled chronic, persistent pain.8-10
The primary objective of this phase I study was to determine the absolute and relative bioavailability of fentanyl delivered by FBT in healthy subjects. Two comparators were used: oral transmucosal fentanyl citrate (OTFC), an approved medication for the treatment of cancer-related breakthrough pain,11 and fentanyl administered intravenously. The study also determined the relative bioavailabilities and the fractions of fentanyl absorbed transmucosally and gastrointestinally from (1) FBT administered transmucosally, (2) FBT taken orally (swallowed), and (3) OTFC administered transmucosally.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Healthy male and female volunteers, aged 18 to 45 years, were screened. Eligible volunteers with a body mass index of 
30 kg/m2 who had normal findings for medical history, physical examination (height, vital signs, and electrocardiogram), and clinical laboratory tests (hematology, serum chemistry, urinalysis, hepatitis B surface antigen screen, hepatitis C antibody screen) within 14 days prior to enrollment were included in the study. Eligible volunteers also had to have negative results at screening for cannabinoids and opioids, have no known positive HIV test result, have a negative serum pregnancy test (women only), and have been nicotine and tobacco free for at least 12 months prior to enrollment. Over-the-counter medications (including herbal supplements) except acetaminophen and ibuprofen were prohibited 7 days prior to dosing and during the study. Monoamine oxidase inhibitors and other prescription medications (with the exception of hormonal contraceptives for women) were prohibited for 2 weeks prior to dosing and during the study. Subjects were not to consume any alcohol or grapefruit juice for 48 hours prior to dosing and during the 72-hour sampling period after each drug administration. Subjects were also excluded if they had a history of frequent or widespread bilateral canker sores, oral herpes, current oral pathology, or presence of dentures or braces that would interfere with tablet placement; any disorder or procedure (including gastrointestinal surgery) that would interfere with drug absorption, distribution, metabolism, or elimination; or blood donation within 56 days or plasma donation within 7 days prior to the screening visit.
Study Design
This was an open-label, 4-period crossover study of FBT (FENTORA, Cephalon, Inc, Frazer, Pa) in healthy adults in which subjects received FBT 400 µg administered transmucosally (FBTTrM), fentanyl 400 µg administered intravenously (fentanylIV), FBT 800 µg administered orally (FBTORAL), and OTFC (Cephalon, Inc) 800 µg administered transmucosally (OTFCTrM) in a randomized fashion. There was a minimum 7-day washout period between each dosing period. The study was conducted by MDS Pharma Services (Phoenix, Ariz).
The selection of dosage strengths was based on pharmacokinetic data obtained in a previous pharmacokinetic study of FBT in healthy volunteers12; data from this study suggested that a 400-µg dose of FBTTrM would provide measurable plasma concentrations of fentanyl through most of the blood sampling period. The doses of fentanylIV 400 µg, FBTORAL 800 µg, and OTFCTrM 800 µg were chosen to achieve comparable systemic exposures to the FBTTrM 400-µg dose.
None of the subjects enrolled in this study were opioid tolerant. Naltrexone hydrochloride 50 mg, an opioid antagonist, was administered at 15 and 3 hours before and 9 hours after administration of each dose of fentanyl to block the opioid receptor-mediated effects of fentanyl.
Study Protocol
Subjects arrived at the center on the day before dosing. Meals were provided, and subjects fasted overnight before dosing. Subjects were given a placebo FBTTrM or a placebo OTFCTrM unit the night before the administration of the respective study drug to allow subjects to become familiar with the correct usage of the tablet or unit. Subjects were instructed to place the FBTTrM tablet between the upper gum and cheek above a molar tooth and allow it to dissolve for 10 minutes. If subjects determined that a portion of the tablet still remained after 10 minutes, they gently massaged the cheek in the area corresponding to the location of the tablet for 5 minutes. If any tablet material remained until 30 minutes after FBTTrM administration, subjects were then permitted to drink 125 mL of water to swallow the remnants. Subjects were instructed to rub the OTFCTrM unit over the mucosal lining of the cheek or suck in a manner that dissolved the unit in as close to 15 minutes as possible. The unit was not to be bitten, chewed, or swallowed.
Subjects were administered 1 of 4 possible fentanyl study drugs at 
0800 hours the next day. When subjects received FBTORAL, the tablet was to be swallowed with 125 mL of water. The intravenous (IV) fentanyl dose was administered via an access catheter placed in the antecubital vein of the forearm. The total IV fentanyl dose was administered in 8 mL of solution over approximately 5 minutes.
Following the administration of any of the 4 fentanyl study drugs, subjects remained seated for 4 hours. After the first hour, subjects were allowed water adlibitum; no other beverages or food were permitted for a minimum of 4 hours following the administration of any of the 4 fentanyl study drugs during each period. Physical activity was generally limited during the confinement periods at the study center. Subjects were monitored in the clinic for 72 hours after fentanyl administration.
Venous blood samples (4 mL) were collected by venipuncture at the following times: immediately before dose administration (hour 0) and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, and 90 minutes and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours after dose administration in each period. After collection, blood samples were inverted slowly 6 to 8 times to mix the contents and placed on ice. Samples were centrifuged (1500g, 15 minutes, 4°C) within approximately 5 to 60 minutes after collection to separate plasma. Plasma samples were frozen at -20°C for up to approximately 10 weeks until analyzed. Plasma concentrations of fentanyl were determined at PPD Development, LP (Richmond, Va) using a validated high-performance liquid chromatography method with tandem mass spectrometric detection (LC/MS/MS). Standard solutions for the analytes were prepared using fentanyl citrate and an internal standard, fentanyl-d5. The mass transitions monitored for analytes were 337.1
188.1 for fentanyl and 342.1188.1 for fentanyl-d5. Samples were processed using liquid-liquid extraction, with evaporation of the extract to dryness and reconstitution of the residue in acetonitrile. Chromatographic separation was by reversed-phase high-performance liquid chromatography using a 2.0 x 150-mm YMC PVA SIL C18 column with 5-µm particles, with multiple-reaction monitoring of the effluent. The linearity of this procedure was evaluated by analyzing 9 calibration standards in duplicate over the concentration range of 0.025 to 10.0 ng/mL using a linear weighted, 1/concentration, least squares regression algorithm to plot the peak area ratio of fentanyl to its internal standard versus concentration. Interassay precision (% coefficient of variation) was <7%, except at the lower limit of quantification, at which it was 16.2%. Interassay accuracy ranged from 94.1% to 102.7%. No interference in the assay was produced by either endogenous species in plasma or naltrexone. Plasma concentrations of fentanyl below the limit of quantitation of the assay (ie, <0.025 ng/mL) were designated as <0.025 ng/mL. For calculating pharmacokinetic parameters, a <0.025-ng/mL value at time 0 or at sampling times before the first quantifiable plasma concentration was treated as 0. All other values <0.025 ng/mL were treated as missing.
Safety and Tolerability
Vital signs (blood pressure, heart rate, and respiration) were taken 30 minutes prior to dosing and at regular intervals during the 72 hours after dosing with a fentanyl study drug. Blood hemoglobin-oxygen saturation monitoring began before and continued for a minimum of 4 hours after each administration of fentanyl. At the completion of the study or at early withdrawal, a 12-lead electrocardiogram, a clinical laboratory evaluation (hematology, serum chemistry, and urinalysis), and a physical examination with vital signs (blood pressure, heart rate, and respiration) were performed.
Subjects were instructed to inform the physician and/or nurses of any adverse events (AEs) that occurred during the study. Evaluation of the subjects' oral mucosa at the site of FBTTrM or OTFCTrM placement was performed at screening, 1 hour after placement of either fentanyl formulation, and at the final assessment. The results of the assessments were recorded.
Pharmacokinetic Analyses
Thirty-two subjects were randomized to sequences of fentanyl study drugs. Twenty-nine subjects received 
1 dose of fentanyl and composed the safety analysis set. The 26 subjects who completed all 4 study periods and received all 4 fentanyl study drugs composed the pharmacokinetic analysis set. After each administration of a fentanyl study drug, the pharmacokinetic parameters for fentanyl were estimated by noncompartmental methods13 using WinNonlin software (Enterprise Version 4.1 [2003], Pharsight Corporation, Mountain View, Calif). All WinNonlin programs used in the analyses were validated prior to use by evaluation of a standard data set. The pharmacokinetic data analysis was conducted using the actual sampling times.
The maximum plasma concentration (Cmax) was the highest observed plasma concentration (obtained without interpolation). The tmax was the time when Cmax was observed. The terminal rate constant for elimination from plasma (
z) was determined by linear regression of the terminal portion of the semilogarithmic plasma concentration versus time curve. The terminal phase was identified for each subject by visual inspection of the data. Due to the incomplete characterization of the terminal elimination phase, z estimates and parameters dependent on z (ie, half-life [t
] and area under the plasma fentanyl concentration vs time curve from time 0 to infinity [AUC0-
]) could not be obtained for all subjects in the pharmacokinetics analysis set. This resulted in a smaller number of subjects for some pharmacokinetic parameters. The terminal elimination t was calculated for each profile as ln(2) divided by z.
The AUCs from time 0 to the 24-hour sampling time, to the 72-hour sampling time, to the time of the median tmax of the FBTTrM group (AUC0-tma
), and to the time of the last measurable concentration (AUC0-t) were determined by linear trapezoidal summation. The AUC from time 0 to infinity (AUC0-) was calculated as the sum of AUC0-t and the area extrapolated from the last measurable plasma concentration to infinity (Clast/z). The percentage of AUC0- extrapolated was calculated as (AUC0- - AUC0-t)/(AUC0-) x 100.
Absolute and relative bioavailability estimates and the fractions of transmucosal FBT and OTFC absorbed transmucosally and through the gastrointestinal tract were calculated. FentanylIV was used as a standard for the comparative calculation of absolute bioavailability of the fentanyl absorbed following transmucosal administration of FBTTrM and OTFCTrM.
Statistical Analyses
The safety analysis group included all subjects who received at least 1 dose of fentanyl. All pharmacokinetic parameters were summarized for each study drug using descriptive statistics, including the geometric mean (if appropriate) and the coefficient of variation. The 95% confidence intervals were determined for all mean ratios by exponentiation of the limits of the confidence interval for the difference of log-transformed means. Assuming an intrasubject standard deviation of the log-transformed data of 0.23, as observed in a previous study,6 and a minimum of 24 subjects completing the study, there was an 80% probability that the error of each of the calculated mean differences on the log-transformed data would be approximately 10%. All data were processed and summarized using SAS Version 8.2.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Profiles
The disposition of fentanyl following the administration of the 4 fentanyl study drugs is in agreement with the published pharmacokinetic profile of fentanyl.14-16 Pharmacokinetic parameters are given in Table I. Even though plasma levels of fentanyl were quantifiable up to 72 hours after administration of all 4 fentanyl study drugs in some subjects, the later portions of the profiles were difficult to characterize for many subjects because plasma concentrations of fentanyl at sampling times of 24 hours or longer were not quantifiable. Mean plasma concentration versus time profiles for the 4 fentanyl study drugs are presented in Figure 1 (up to 12 hours). The mean plasma concentration versus time profiles observed following administration of FBTTrM 400 µg or FBTORAL 800 µg were characterized by a rapid absorption phase (median tmax = 47 minutes and 90 minutes, respectively), a biexponential decline from Cmax (1.02 ng/mL and 0.98 ng/mL, respectively), and median t of 14.4 and 15.4 hours, respectively. However, individual profiles for approximately half of the subjects who received FBTTrM or FBTORAL depicted a triexponential decline. Following administration of OTFCTrM 800 µg, the median tmax occurred at approximately 91 minutes followed by a biexponential decline from Cmax (1.26 ng/mL), with a median t of 18.3 hours. Following fentanylIV 400 µg, the mean pharmacokinetic profile followed a triexponential decline from Cmax (3.00 ng/mL) at a median t of 17.6 hours.
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Absolute Bioavailability
Absolute bioavailability was assessed following normalization of the pharmacokinetic variables to a 400-µg dose of fentanyl. FBTTrM was observed to have greater absolute bioavailability (FFBT = 0.65) than OTFCTrM (FOTFC = 0.47) or FBTORAL (FORAL = 0.31) based on ratios of the respective AUC0- values to the AUC0- value of fentanylIV (Table II). The observed greater absolute bioavailability is a result of the higher proportion of fentanyl being absorbed across the oral mucosa after FBTTrM than after OTFCTrM administration. For FBTTrM, approximately 50% of the total dose was absorbed across the buccal mucosa (fTrM(FBT) = 0.48) and became systemically available. The remaining half of the total FBTTrM dose was swallowed and slowly absorbed from the gastrointestinal tract (fG(FBT) = 0.52). Approximately one third (FORAL = 0.31) of the amount swallowed escaped gastrointestinal and hepatic first-pass elimination and became systemically available. A lower fraction of the total OTFCTrM dose was absorbed through the buccal mucosa (fTrM(OTFC) = 0.22), with approximately 80% of the dose swallowed and absorbed from the gastrointestinal tract (fG(OTFC) = 0.78).
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Relative Bioavailability
The differences in absolute bioavailability and the relative fractions absorbed across the mucosa and gastrointestinal tract between FBTTrM and OTFCTrM explain the differences observed in early systemic exposure to fentanyl. Based on dose-normalized values (to 400 µg, Table III), a higher early systemic exposure to fentanyl was observed with FBTTrM than with OTFCTrM (Figure 2A), as measured by AUC0-tma and Cmax. Similarly, a greater total systemic exposure to fentanyl, as measured by AUC0-, was observed after administration of FBTTrM than OTFCTrM.
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Early systemic exposure to fentanyl was also assessed following normalization to comparable peak plasma concentrations of fentanyl. Following normalization to Cmax of 1.02 ng/mL for FBTTrM and 0.94 ng/mL for OTFCTrM, FBTTrM was observed to have higher early exposure than OTFCTrM (AUC0-tma = 0.40 and 0.21 ng·h/mL, respectively; Figure 2B).
Safety and Tolerability
All reported AEs were mild to moderate in nature. Although AEs that occurred after naltrexone but before administration of a fentanyl study drug may be attributable to naltrexone, those that occurred after administration of any of the fentanyl study drugs could not be attributed definitively to either. One subject reported a mild AE (nausea following administration of fentanylIV) that caused withdrawal from the study. No AEs related to the application site were reported by the subjects or observed during the evaluation of the oral mucosa performed 1 hour after placement of either FBTTrM or OTFCTrM or at the final assessment. There were no clinically meaningful changes from baseline values in results related to vital signs, electrocardiogram, serum chemistry, urinalysis, or hematology.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Although both formulations are designed for the transmucosal delivery of fentanyl, the rate and extent of fentanyl absorption reported in this study were different following administration of FBTTrM compared with OTFCTrM. Median tmax occurred more quickly for FBTTrM compared with OTFCTrM (median tmax, 47 vs 91 minutes, respectively). Although a range of 20 to 40 minutes for median tmax for OTFC has been observed in previously published studies,17-19 the current intrastudy comparison of median tmax data between FBTTrM and OTFCTrM is more compelling than comparisons across studies. Support for the results regarding the comparison of median tmax data between FBT and OTFC in the current study can be drawn from a recently published study20 comparing the relative bioavailability of the 2 drugs at higher doses. Although the methodology used in the published study was not as sophisticated as the methodology used in the current study, administration of FBT 1080 µg yielded higher early systemic exposure of fentanyl compared with OTFC 1600 µg, as measured using median tmax (1.0 vs 2.0 hours, respectively; P < .001). The observed time differential for median tmax between FBT and OTFC in the published study20 (ie, approximately half the time) is similar to that observed in the current study. Additional support for the comparison of median tmax between FBT and OTFC can be drawn from another article,7 which showed a median tmax of 0.5 hours for FBT 200 µg compared with 2 hours for OTFC 200 µg (P < .003). The fraction of the FBTTrM dose absorbed transmucosally was 48% of the total dose in the current study, and the fraction of the OTFCTrM dose absorbed transmucosally was 22% of the total dose. As a result, a higher absolute bioavailability was seen following administration of FBTTrM (65%) when compared with OTFCTrM (47%). The absolute bioavailabilities calculated for OTFCTrM (FOTFC = 0.47) and FBTORAL (FORAL = 0.31) are consistent with previously published bioavailability values for OTFC and an oral solution of fentanyl.17
Upon dose normalization to equal doses (400 µg), a higher exposure to fentanyl was observed following administration of FBTTrM compared with OTFCTrM (as measured by Cmax, AUC0- [total systemic exposure], and AUC0-tma [early systemic exposure]). Following normalization to comparable Cmax values, greater earlier systemic exposure (as measured by AUC0-tma) was seen following administration of FBTTrM than following OTFCTrM. On the basis of these comparisons, an approximately 30% smaller dose of FBT would achieve systemic exposures comparable with those observed following administration of OTFC. These data suggest that physicians should consider the implications of these differences between FBTTrM and OTFCTrM when selecting dose regimens or switching between these 2 formulations.
After administration of OTFCTrM or FBTORAL, plasma concentrations of fentanyl were observed to decline biexponentially from peak concentrations. When full characterization of the terminal elimination phase was possible following administration of FBTTrM or fentanylIV, plasma fentanyl concentrations were observed to decline from peak mean Cmax in a triexponential manner. The observed difference between the shapes of the mean profiles is attributable to the slower absorption of OTFCTrM and FBTORAL as compared with FBTTrM and fentanylIV. The slower absorption masks the early distribution phase. Fentanyl is known to exhibit a triexponential decline from peak plasma concentration following absorption.14-16
Pharmacokinetic data were available for 26 subjects, a sample size providing adequate power to assess bioavailability. A limitation of the study was the timing of venous sampling and determination of true Cmax for the transmucosal study drugs. Although venous samples were drawn every 5 minutes for the first 50 minutes after study drug administration and at variable times after 50 minutes, the true Cmax could have theoretically been missed; however, the study was designed to determine the closest approximation of Cmax. The pharmacokinetic profile of FBT in actual clinical use may differ under certain circumstances from that seen in this study, particularly in patients with hepatic impairment or in those receiving concomitant medications affecting cytochrome P450 3A4 activity, which is largely responsible for first-pass metabolism of fentanyl.21
In this study, the rate and extent of absorption, and therefore the absolute bioavailability, of fentanyl were greater following transmucosal administration of FBT as compared to OTFC. On the basis of comparisons conducted, an approximately 30% smaller dose of FBT would achieve systemic exposures comparable with those following administration of OTFC. In conclusion, these data indicate that the differences between FBT and OTFC in absolute bioavailability and in the fractions absorbed transmucosally must be taken into account when selecting dose regimens or switching between these formulations.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: All authors are employed by Cephalon, Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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19. Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate. Anesthesiology. 2004;101: 729-737.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Darwish M, Tempero K, Kirby M, Thompson J. Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1080 µg versus oral transmucosal fentanyl citrate 1600 µg and dose proportionality of FEBT 270 to 1300 µg: a single-dose, randomized, open-label, three-period study in healthy adult volunteers. Clin Ther. 2006;28: 715-724.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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