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PHARMACOKINETICS |
From the MDS Pharma Services, Montreal (St-Laurent), Quebec, Canada (Dr Marier, Ms Lor, Ms Potvin, Dr DiMarco, Dr Morelli) and Nycomed, Roskilde, Denmark (Dr Sædder).
Address for reprints: Eva Aggerholm Sædder, MD, Nycomed, International Medical Affairs, Langebjerg 1, Postbox 88, 4000 Roskilde, Denmark; e-mail: evs{at}nycomed.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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) and peak concentrations (Cmax) of the matrix formulation were 84 838 pg·h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUC and Cmax between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.
Key Words: Fentanyl • matrix transdermal delivery system • pharmacokinetics • tolerability
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For this reason, a second generation of patches with a matrix-type design was developed. In the matrix patch, the drug is completely dissolved in the semi-solid formulation of a polyacrylate adhesive. This method complicates the extraction of the drug by purpose to minimize drug abuse and furthermore completely diminishes the risk of incidental drug leakage. The constituents of this novel matrix delivery system with a rate-controlling membrane are represented schematically in Figure 1 (panel B). The outer backing film (A) is a transparent, inert, and occlusive siliconized polyester layer protecting the matrix formulation. In this type of delivery system, the drug is dispersed in a semisolid formulation within the adhesive itself, but the drug-containing matrix (B) consists of fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix formulation. This special formulation improves the control of drug release to the extent that the drug load in the matrix patch with dipropylene glycol droplets is reduced by almost 35% compared with other matrix formulations previously developed. The rate-controlling membrane (C) is a copolymer of ethylene and vinylacetate (EVA). It ensures that fentanyl concentrations are maintained at a more constant level throughout a 72-hour application of the patch. In addition, the membrane helps to stabilize the patch and makes the patch easier to handle. The skin adhesive layer (D) is a silicone adhesive with excellent skin compatibility16; the adhesive is gentle and soft when in contact with skin and is expected to cause no irritation on removal. The release liner layer or removable protective film (E) is provided with a practical slit line that supports the easy application of the patch. The release liner must be peeled off before applying the patch to the skin. The combination of the EVA membrane and the special matrix formulation allows for a highly efficient degree of drug utilization, which in turn means that a substantially lesser load of fentanyl is required for this special matrix type as compared to the conventional matrix type with a drug completely dissolved in the adhesive itself. Given its smaller size, the novel matrix formulation is discreet, flexible, and easy to handle.
The objectives of the present study were to determine the pharmacokinetics and tolerability of the novel matrix transdermal system of fentanyl after repeated 72-hour applications in healthy subjects and compare its overall performance to the commercialized available reservoir product by characterizing adherence, skin irritation, and amounts of fentanyl delivered from the 2 formulations.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Before the study start, all volunteers gave informed consent according to local requirements. All subjects were aged between 18 and 45 years, weighed at least 60 kg and had normal body mass indexes (18-27 kg/m2). Subjects were medically healthy with clinically normal electrocardiograms (ECGs) and had normal laboratory tests, with no history of alcohol and drug abuse. The protocol and Informed Consent Form were submitted and accepted by the Institutional Review Board. The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, relevant European Union guidelines, and any regulations for the protection of personal data.17 Subjects were not allowed to participate in the clinical study if they had (1) certain types of disease (cardiovascular, pulmonary, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease); (2) skin lesions on arms or diffuse skin diseases (diffuse psoriasis or eczema); (3) hairy skin; (4) extensive tattooed areas on upper arms; (5) history or presence of alcoholism or drug abuse; (6) hypersensitivity or idiosyncratic reaction to fentanyl, other opioids, any component of the Durogesic patch system (Janssen-Cilag, Beerse, Belgium), adhesive dressing, or medical tape; (7) sitting blood pressure of less than 110/60 mm Hg at screening; (8) a pulse less than 55 beats per minute at screening; (9) alaninaminotransferase values greater than 1.5 times the upper limit of normal; (10) used drugs or substances known to be strong inhibitors of cytochrome P450 (CYP) enzymes within 10 days of study start; (11) used any drugs or substances known to be strong inducers of CYP enzymes within 28 days of study start; (12) an abnormal diet (for whatever reason) during the 28 days preceding the study; (13) concomitant medication with monoaminooxydase inhibitors; and (14) participated in other clinical trials within 28 days before the first dose. No subjects were allowed to take medication (including over-the-counter products) for the 7 days preceding the study. This prohibition did not include vitamins taken as nutritional supplements for nontherapeutic indications, as judged by the attending physician. Consumption of foods and beverages containing xanthines (24 hours before dosing and throughout the period of sample collection), alcohol (48 hours before dosing and throughout the period of sample collection), and grapefruit (10 days before dosing and throughout the study) were prohibited as indicated.
Treatments and Formulations
Subjects were randomly assigned to receive the reservoir transdermal delivery system (Durogesic; 50 µg/h; 5.0 mg fentanyl patch; reservoir size, 20 cm2; total patch size, 34 cm2; Janssen-Cilag) or the novel matrix transdermal delivery system (50 µg/h; 5.5 mg matrix fentanyl patch with controlled membrane; total patch size, 16.8 cm2; Nycomed Group, Roskilde, Denmark), according to a balanced 2-way crossover study design. A naltrexone challenge test for diagnosis of any physical opioid dependence was performed approximately 15 hours before the first patch application by the administration of 50 mg naltrexone (Revia, 1 x 50 mg tablet, Duramed Pharmaceuticals, Cincinnati, Ohio). To prevent opioid adverse drug reactions, all subjects received an oral dose of 50 mg naltrexone (Revia, 1 x 50 mg table) once daily at a 24-hour interval (starting on the morning of day 1 until the morning of day 11) in each period. Naloxone treatments (Narcanti, solution for injection, 0.4 mg/mL, Bristol-Myers Squibb, New York, New York) were available at all time as an emergency antidote medication in cases of severe opioid adverse drug reactions. The patches were applied on nonirritated, nonirradiated, and tattoo-free skin on the upper nondominant arm. Hair was carefully clipped before patch application to allow adequate adhesion of the patch. Within an hour before dosing, skin was washed with only water and was dried gently before application. Patches were applied immediately after removal from the package. Patches were pressed firmly in place with the palm of the hand for 30 seconds. When applying, gloves were worn to avoid contact with the drug containing gel. The new patch was applied to a different area of skin after removal of the previous patch (the contralateral arm).
Tolerability
Vital signs (respiratory rate, blood pressure, and pulse) were recorded before the first patch application and at the following time points after the first patch application: 2, 4, 8, 12, 24, 36, 48, 60, 72 (before the second patch application), 84, 96, 108, 120, 132, 144 (before the third patch application), 156, 168, 184, 192, 208, 216, 228, 240, 264, and 288 hours. Electrocardiograms were obtained before patch application every 24 hours after the first patch application until 24 hours after the last patch removal (10 days after dosing). Readings of oxygen saturation and respiratory rate were performed up to 24 hours after the last patch removal. All adverse events recorded throughout the study were evaluated by a physician.
Blood Sampling and Patch Performance Assessment
Because of the sensitivity of fentanyl to light, blood samples were collected and were processed under conditions that minimized their exposure to light. Blood samples (7 mL each) for pharmacokinetics were collected in Vacutainers tubes with no additives before the first patch application (time 0) and at 12, 24, 36, 48, 60, 72 (before the second patch application), 84, 96, 108, 120, 132, 144 (before the third patch application), 146, 148, 152, 156, 160, 168, 176, 184, 192, 200, 208, 216, 228, 240, 264, and 288 hours after the first application. Each period consisted of 3 patch applications, and transdermal systems were removed after 72 hours (at 72, 144, and 216 hours) in each treatment period. Blood samples were allowed to clot at room temperature (maximum time 60 minutes) and then centrifuged at 3000 rotations per minute (rpm) for 7 minutes at 4°C. All serum samples were divided into 2 aliquots of approximately 0.9 mL each. Serum samples were stored in MDS standard barcode-labeled tubes (MDS Pharma Services, Montreal, Quebec, Canada) at -20 ± 10°C, within 90 minutes of collection, pending assay. The location of the venipuncture varied from one draw to the next to minimize subject discomfort. After patch removal, the application site was wiped with a swab to remove any residual fentanyl remaining on the skin. Once removed, patches were placed in the original sachets and stored in labeled plastic bags.
Adhesive properties of each patch were graded every 12 hours (within approximately 10 minutes) starting at time 0 up to and including 72 hours post-dose (before patch removal) after the application of the first, second, and third patch. The area of the patch was divided into squares of equal size, forming a grid. This grid was used to determine the number of squares remaining adhered to the skin, and a percentage of adhesion was calculated every 12 hours. A global percentage of adhesion was calculated by pooling all individual results measured during the 72-hour application of the first, second, and third patch in a specific subject. Assessment of skin irritation was performed immediately after removal of the first, second, and third patches (ie, at 72, 144, and 216 hours, respectively), 24 hours after their removal (ie, at 96, 168, and 240 hours, respectively) and 48 hours after their removal (ie, at 120, 192, and 264 hours, respectively). Assessment of skin irritation was performed immediately after a blood draw. The assessment of skin irritation of a particular patch was not affected by the application of a subsequent new patch because the new patch was applied to a different area on the opposite arm. Skin irritation of the 2 delivery systems was evaluated using Skin Irritation Scoring Systems.18 The test was graded according to the following skin irritation grading scales. The following dermal response was used: 0, no evidence of irritation; 1, minimal erythema, barely perceptible; 2, definite erythema, readily visible with minimal edema or minimal papular response; 3, erythema and papules; 4, definite edema; 5, erythema, edema, and papules; 6, vesicular eruption; 7, strong reaction spreading beyond test site.
Analytical Methods
Fentanyl concentrations in serum samples were determined by a sensitive and specific method using liquid chromatography with mass spectrometry detection (LC/MS/MS) developed at MDS Pharma Services. Fentanyl was extracted from human serum samples by a cohesive on-line automated extraction method. Briefly, 100 µL of the internal standard working solution (5.00 ng/mL fentanyl-D5) was added to 100 µL of each serum sample, and the tubes were vortexed. A volume of 200 µL was then transferred onto a Millipore Multiscreen 1.2 µm filtration plate (Millipore Corp, Billerica, Mass), and the samples were centrifuged at 2000 rpm for 5 minutes at 20°C. Samples from the collection plate were injected into the TurboFlow 2300 HTLC system (Cohesive Technologies, Franklin, Mass). The HTLC setup consisted of an HTS PAL LEAP autosampler (CTC Analytics, Zwingen, Switzerland), an API 3000 detector (PerkinElmer Sciex, Woodbridge, Canada), and a data system analysis (Quadra Power PC, Apple Computer, Markham, Canada). Each sample was trapped on a Cyclone HTLC column (50 x 1mm x 50 µm, Cohesive Technologies) with a loading flow rate of 3.0 to 5.0 mL/min and an elution flow rate of 1.0 mL/min. The loading phase consisted of 2 different solvents (25 mM ammonium acetate in water and a 90:10 mixture of methanol with 25 mM ammonium acetate in water). The flow from the column was split 1:5 into a PE Sciex API 3000 triple quadrupole mass spectrometer (PerkinElmer Sciex) equipped with a Turbo Ionspray source operating at 450°C. Fentanyl and fentanyl-D5 were monitored in a positive mode under MS/MS conditions. The retention times for fentanyl and fentanyl-D5 were 1.94 minutes and 1.92 minutes, respectively. Human serum lots, free of significant interference, were pooled and were used to prepare calibration standard and quality control samples. Appropriate dilutions were performed when concentrations fell outside the analytical range (10-4000 pg/mL). Linearity was assessed by plotting area ratios versus standard concentrations and using a linear regression weighted 1/concentration2. During validation, the correlation coefficients ranged from 0.9957 to 0.9986 for 3 batches. The interbatch and intrabatch precision and accuracy of the assay were assessed with 4 levels of quality control samples (10.0, 30.9, 309.2, and 3091.9 pg/mL) with 6 samples for each quality control for a total of 24 quality controls. The inter-batch coefficient of variation (CV%) ranged from 3.7% to 16.7%, interbatch accuracy ranged from 100.1% to 114.0%, intrabatch CV% ranged from 1.3% to 9.2%, and intrabatch accuracy ranged from 87.0% to 105.8% for all 4 quality control samples. The limit of quantitation was 10 pg/mL.
Residual fentanyl patch content was determined using a validated high-performance liquid chromatography (HPLC) with ultraviolet detection based on a method previously published.19 Briefly, the protective foil was removed from the patch and the patch reservoir carved multiple times with the use of a scalpel to facilitate the extraction of the drug. Once carved, the patch was placed in an Erlenmeyer flask. A specific volume of 2-propanol was added to the flask, depending on the initial drug content of the patch. The flask was stopped and was stirred with a magnetic stirrer at approximately 200 to 250 rpm for a minimum of 16 hours. An aliquot of the sample solution was then centrifuged for an additional 10 minutes at 12 000 rpm. The supernatant solution was then transferred into an HPLC vial for analysis. After injection of 3 levels of quality control samples in triplicate, recovery of fentanyl ranged from 93.1% to 110.7%. The intrabatch CV% of the assay based on the injection of 6 quality control samples was 6.9%, and mean accuracy was 101.3%.
Pharmacokinetics and Statistics
The following pharmacokinetic parameters were calculated over the last 72-hour application interval: the area under the curve (AUC), the maximum serum concentration (Cmax), the minimum serum concentration (Cmin), the time of maximum serum concentration (tmax), the apparent first-order terminal elimination rate constant (Kel), the apparent first-order terminal elimination half-life (t
, calculated as 0.693/Kel), and fluctuation [calculated as (Cmax - Cmin)/Cav], where Cav is calculated as AUC divided by the dosing interval.20
Analyses of variance (ANOVA) were performed on natural log-transformed (AUC, Cmax, and Cmin) and untransformed (tmax, t, and fluctuation) pharmacokinetic parameters of fentanyl between the 2 delivery systems. The ANOVA model included sequence, subjects nested within sequence, period, and drug formulation as factors. The significance of the sequence effect was tested using the subjects nested within sequence as the error term. A 5% level of significance was for within-subject comparisons (ie, period, formulation) and a 10% level of significance for between-subject comparisons (ie, sequence). Analysis of variance included calculation of least-squares means (LSM), adjusted differences between formulation means and the standard error associated with these differences. Statistical analyses were performed using the SAS GLM procedure (SAS Institute, Cary, NC).
Residual amounts of fentanyl from the matrix and reservoir delivery systems were assayed directly from the patch. Actual amounts of fentanyl delivered from the patch were calculated by subtracting the measured residual amounts of fentanyl from the nominal amount of fentanyl (label claim) in the matrix (5.5 mg) and reservoir (5.0 mg) delivery systems. The same ANOVA model as above was performed on natural log-transformed residual and delivered amounts. The percentage of adherence was calculated by dividing the number of squares remaining adhered by the total number of squares on the grid. Adhesion was scored as a percentage of completely adhered squares. Scores of adhesiveness and skin irritation were analyzed using the same ANOVA model using untransformed data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Overall, all vital signs and ECGs were within normal range during the study. The application of the novel matrix and reservoir delivery systems of fentanyl did not depress respiratory rate or hemoglobin oxygen saturation. A summary of adverse events associated to the matrix and reservoir delivery systems is presented in Table I. Twenty-four subjects (100%) reported 395 adverse events during this study: a total of 215 (54%) adverse events occurred with the novel matrix delivery system, and 180 (46%) adverse events occurred with the reservoir delivery system. The number of subjects reporting at least 1 adverse event was roughly equal between treatment groups, as 23 and 21 subjects reported at least 1 adverse event while receiving the matrix and the reservoir delivery system, respectively. Of the 395 adverse events observed in the study, 248 (60%) were localized to the application site, with 115 (45%) of these observed for the matrix delivery system, and 133 (55%) observed for the reservoir delivery system formulation. Application site adverse events included burning, dermatitis, erythema, pain, papules, pigmentation changes, pruritus, and swelling. The majority of adverse events (98%) were mild in severity. One adverse event (application site erythema, reservoir formulation) was judged severe. Of the 8 adverse events considered moderate in severity, 5 (vomiting, nausea x 2, candidiasis, and headache) occurred with the novel matrix formulation and 3 (erythema, excoriation, and headache) occurred with the reservoir formulation. No serious adverse events occurred.
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and Cmax were within 80% to 125%, confirming that both formulations displayed similar rate and extent of fentanyl bioavailability. Mean clearance values of fentanyl in the current study for the matrix and reservoir formulations (42.4 and 41.0 L/h, respectively) were consistent to that observed in cancer patients (41 L/h).21 Maximum serum concentrations for the matrix and reservoir formulations were observed at 28.0 and 26.8 hours on the last day of treatment, respectively. Minimum serum concentrations of fentanyl were in the same range for the 2 patch formulations (678 and 647 pg/mL, respectively). The observed mean value of t for the novel matrix delivery system was approximately 30% longer than that observed for the reservoir formulation because of an unexpected longer t measured in 1 subject. (ie, t of 85 hours). On the other hand, the median values of t for the matrix and reservoir formulations were consistent (30.7 and 27.4 hours, respectively), suggesting that a single t in 1 subject could have skewed the calculation of the arithmetic mean for the matrix formulation.
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Mean (±SEM) percentages of adherence after the 72-hour application of the first, second, and third matrix and reservoir formulations are presented in Figure 3. Overall, the percentage of adherence of the 2 formulations was higher within the first 24 hours after application of the first, second, and third patch. Mean percentage of adherence fell below 50% 72 hours after patch application for both formulations. The distribution of individual skin irritation scores after removal of the first, second, and third reservoir and matrix formulations are presented in Figure 4. Immediately after removal of the first, second, and third reservoir and matrix formulations (ie, at 72, 144, and 216 hours, respectively) the vast majority of subjects experienced irritation scores of 1 (ie, minimal erythema). Approximately 48 hours after removal of the first, second, and third patch (ie, at 120, 192, and 264 hours, respectively), the majority of subjects experienced irritation scores of 0 (ie, no evidence of erythema). Irritation scores of 2 (ie, definite erythema) or 3 (ie, erythema and papules) were experienced by a few subjects only. Irritation scores of 4, 5, 6, or 7 were not observed during the study. A summary of results of performance parameters for the matrix and reservoir delivery system are presented in Table III. Global adhesion scores were calculated by pooling all results measured over the 72-hour application of the first, second, and third patch. The difference in percentage of adherence between the matrix and reservoir formulation (62.5% vs 56.2%, respectively) remained small but statistically significant (P < .0001) because of the low variability observed for the 2 formulations (19.4% vs 21.0%, respectively). The difference in adherence between the 2 formulations did not appear to affect the absorption of fentanyl because no correlation was observed between adherence scores and pharmacokinetic parameters of fentanyl. Mean skin irritation scores for the novel matrix and reservoir delivery systems were not statistically different. Because the label claim (nominal amounts of fentanyl) for the matrix formulation is 5.5 mg and the reservoir formulation is 5.0 mg, the residual amounts of fentanyl from the novel matrix formulation were also higher than those measured for the reservoir formulation. As a result, the amount of fentanyl delivered from the matrix and from the reservoir formulations was not statistically different (4.21 and 4.32 mg, respectively).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The first type of patch used for the transdermal delivery of fentanyl, steroid hormones, nicotine, and scopolamine were based on the reservoir technology.10-12 A growing number of transdermal systems based on the matrix technology were developed for the delivery of steroid hormones and other drugs such as buprenorphine and nitroglycerin.24-26 To determine the pharmacokinetics, tolerability, and performance of the novel matrix transdermal delivery system of fentanyl, a total of 20 healthy male subjects received repeated 72-hour applications of 50 µg/h of fentanyl as the novel matrix and reservoir formulations in a randomized, 2-way crossover study. Patch adherence, skin irritation, and amounts of fentanyl delivered were evaluated. Application of 3 consecutive patches was judged to be sufficient to reach steady-state serum concentrations of fentanyl and also by considering how long it was justifiable to treat healthy subjects with transdermal fentanyl. To reduce the risk of adverse events due to the duration of the treatment period, a dose of 50 µg/h was chosen. The effects and potential risks of fentanyl were to be countered by pretreatments of the opiate antagonist naltrexone hydrochloride. Naltrexone is known to attenuate or completely block the subjective effects of intra-venously administered opioids and block the physical dependence to morphine, heroin, and other opioids in a reversible manner.27 In the current trial, all subjects received a 50-mg oral dose of naltrexone per day, which appeared to be sufficient to prevent major opioid-related adverse drug reactions to fentanyl such as hypoventilation and withdrawal symptoms. Overall, mean clearance values of fentanyl from the current study (ie, healthy subjects receiving concomitant naltrexone) were consistent to those observed in cancer patients, suggesting that naltrexone did not affect the pharmacokinetics of fentanyl.21 The emergency antidote naloxone was not used because no severe opioid drug reactions were observed during the study.
The novel matrix and reservoir transdermal delivery system of fentanyl appeared to be safe and equally well tolerated by this group of healthy male subjects. The majority of adverse events experienced during this study were related to the patch application site, and their frequency was approximately equal between the 2 delivery systems. The most common adverse event was erythema at the application site, which also occurred at equal frequency between the reservoir and the novel matrix transdermal delivery system.
Multiple blood samples were collected throughout the study, and serum concentrations of fentanyl were assayed. Pharmacokinetic profiles of fentanyl after application of the reservoir and matrix formulations were superimposable throughout the whole study. Overall, serum fentanyl concentrations declined in a log-linear manner after removal of the transdermal system on the last day of treatment. Pharmacokinetic parameters of fentanyl after the application of the reservoir and matrix formulations were very similar. Ratio of LSM and 90% confidence interval of AUC and Cmax were within 80% to 125%, confirming that the 2 delivery systems displayed equivalent rates and extent of bioavailability of fentanyl. A fundamental assumption of clinical pharmacology is that there is always a relationship between the toxicity or efficacy of a drug and drug concentration at the sites of toxicity or efficacy. Assuming that both drug formulations reach the systemic circulation before moving to their sites of efficacy and toxicity, if their systemic concentration-time profiles are identical, then the efficacy and toxicity resulting from their pharmacokinetic profiles will also be identical. As a result, the 2 delivery systems were bioequivalent considering that they resulted in identical systemic concentration-time profiles, understanding that once the drug itself reaches the systemic circulation, its pharmacokinetic behavior (distribution and elimination) will be the same between the 2 different transdermal delivery systems. Based on these assumptions, the 2 delivery systems are expected to produce identical pharmacologic effects.
To determine the patch adherence capacity of the novel matrix delivery systems, adhesive properties of each patch were graded every 12 hours during the whole study. The novel matrix formulation resulted in a statistically higher patch adherence than that observed for the reservoir delivery system, without enhancing skin irritation or affecting the pharmacokinetics of the drug. Overall, the matrix formulation tends to be more discreet than the reservoir formulation based on its smaller size (16.8 vs 34 cm2, respectively). Although compliance was not directly assessed in the current study, the smaller size and enhanced adherence profile of the matrix formulation may be factors that will have an impact on treatment compliance. At the end of the study, residual amounts of fentanyl were assayed from the 2 different transdermal delivery systems. Residual amounts of fentanyl from the novel matrix formulation were higher than those measured for the reservoir formulation because the label claim for the matrix formulation (5.5 mg) was higher than that for the reservoir (5.0 mg) formulation. As a result, the amounts of fentanyl delivered from the matrix and reservoir formulations were not statistically different (4.21 and 4.32 mg, respectively). The concentration gradient existing between the saturated solution of fentanyl in the reservoir and the concentration in the skin drives the rate of release of fentanyl from transdermal delivery systems. As a result, each patch contains many-fold more drug than the actual amount delivered during a dosing interval (5.0 mg vs 50 µg/h for 72 hours) to create the gradient necessary to keep a constant rate of release. Because of this finding, the reservoir transdermal delivery system of fentanyl creates unique opportunities for use and abuse. Several methods of abuse of this analgesic have been reported, ranging from ingestion to inhalation to application of multiple patches to the skin.28 Even though there is a higher amount of fentanyl available for abuse and misuse after 3 days of therapeutic use of the novel matrix delivery system as compared to the commercially available reservoir formulation, the possibilities for extraction of the residual amount are limited in the matrix formulation as compared to the reservoir formulation. However, caution is required for the disposal of the novel matrix patch, as well as for the reservoir patch.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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