Transdermal Therapy for Overactive Bladder: Present and Future

TREATMENT OF OVERACTIVE BLADDER Transdermal Therapy for Overactive Bladder: Present and Future Victor W. Nitti, MD Department of Urology, New York University School of Medicine, New York, NY Transdermal delivery of certain pharmacologic agents offers distinct advantages, including the ability to bypass the gastrointestinal environment, fewer side effects, and increased bioavailability. For many patients with overactive bladder (OAB), transdermal therapy is more convenient than oral therapy, and the altered drug metabolism offers the advantages of an improved side-effect profile and enhanced steady-state plasma concentrations. The “newness” of transdermal delivery to physicians treating OAB is a potential limitation; however, much insight can be gained from the successful use of transdermal systems for delivery of other therapies, such as agents for chronic pain, hormone replacement therapy, and contraceptives. The transdermal oxybutynin system for OAB reduces the level of oxybutynin metabolites, resulting in a low incidence of anticholinergic side effects, and provides efficacy similar to that of standard doses of currently available oral preparations. However, there is room for improvement of the transdermal system, especially with respect to providing increased efficacy over currently available oral medications and reducing and treating local skin reactions at the application site. [Rev Urol. 2003;5(suppl 8):S31-S36] © 2003 MedReviews, LLC Key words: Transdermal drug delivery • Overactive bladder • Oxybutynin • Skin reactions ver the past decade, there has been an increased focus on the potential of transdermal drug delivery, which has resulted in a plethora of innovative research. In 2001, Barry1 reported that 40% of drug delivery candidate products that were under clinical evaluation and 30% of those in preclinical development in the United States were transdermal or dermal systems. For several O VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S31 Transdermal Therapy for OAB continued years, transdermal delivery has been an accepted mode of administration for hormone replacement therapy (HRT). It is also gaining an increasing role in the treatment of chronic pain and for contraception. Recently, transdermal delivery of oxybutynin was introduced for the treatment of overactive bladder (OAB). Although transdermal delivery theoretically offers distinct advantages over oral delivery for certain compounds in certain patients, its ultimate impact on the treatment of chronic conditions such as OAB remains to be seen. This is primarily because of the aversion of some patients and physicians toward transdermal patches, the most common form of transdermal drug delivery. In addition, because of the novelty of this modality in many therapeutic areas, there is a lack of understanding on the part of both patients and physicians. We might better understand the potential benefits and role of transdermal systems by considering the experience already gained with those currently available, particularly with respect to patient and physician satisfaction. It is important for urologists, as leaders in the treatment of OAB, to understand the advantages and disadvantages of transdermal therapy in general and for OAB specifically. Furthermore, some insights into how transdermal therapy can be enhanced in the future will provide an even greater understanding of its potential. Acceptance of and Satisfaction With Transdermal Therapy Transdermal HRT has been available for years and is an accepted alternative to oral therapy. Although there have been numerous studies comparing transdermal and oral HRT with respect to a variety of efficacy variables, there have been surprisingly few studies focusing on patient preference S32 VOL. 5 SUPPL. 8 2003 and satisfaction. Ettinger and colleagues2 found that the relative risk of discontinuation was higher for transdermal estradiol (2.7) than for oral conjugated estrogens in women aged 45 years or older who filled their first prescription in 1995 in the Kaiser Northern California health system. All women were taking continuous or cyclical medroxyprogesterone. Twenty-five percent of those starting on oral therapy switched to transdermal therapy versus 0.9% who switched from transdermal to oral therapy. In this study, patients could not appreciate the full benefits of transdermal estrogen, as they still needed to take oral progesterone. In a more recent report, Lake and Pinnock3 compared 2 different types of estradiol, matrix versus reservoir, transdermal fentanyl versus oral sustained-release morphine for the treatment of non-cancer pain. In an open-label randomized study, patients received a fixed dose of either medication for 4 weeks, followed by 4 weeks of the other therapy. Preference was assessed in 85% of 256 patients: 65% preferred or very much preferred transdermal therapy and 28% preferred oral therapy (P < .001); 7% expressed no preference. Quality-oflife scores were higher in the group receiving transdermal therapy. Contraception is the newest area in which transdermal delivery is becoming a major player. Since its introduction in 2002, the Ortho Evra™ once-weekly patch (Ortho-McNeil Pharmaceutical, Raritan, NJ) has become the fastest growing contra- Available data suggest that, for chronic pain therapy and contraception, the acceptance of transdermal therapy is growing because of its convenience and decreased incidence and impact of side effects. in 35 hysterectomized women who received 4 weeks of each therapy. Eighty-seven percent of patients selected the matrix patch as their preferred treatment because it was easy to remember, open, and apply and had better adhesion and cosmetic appearance. Of 27 subjects who stated a preference, 74% preferred transdermal to oral therapy. Transdermal therapy has also become popular for the treatment of chronic cancer-related and non-cancer pain. Two studies on chronic pain in patients with advanced cancer showed a patient preference for transdermal fentanyl over sustained-release oral morphine.4,5 Although both treatments resulted in similar relief of pain, transdermal fentanyl was associated with a lower frequency and reduced impact of side effects. Allan and colleagues6 studied REVIEWS IN UROLOGY ceptive on the market. Both the North American7 and European8 phase 3 comparative trials showed superior compliance with patch versus oral contraceptives, with a significantly higher number of cycles with perfect compliance (88.7% vs 79.2%; P < .001 in the North American trial). A subanalysis of the North American data showed that compliance with the patch was consistent across age groups but differed significantly by age for oral therapy, with younger patients having a lower percentage of cycles with perfect compliance.9 Transdermal therapy has become popular for the treatment of several “chronic” conditions. Available data suggest that, for chronic pain therapy and contraception, the acceptance of transdermal therapy is growing because of its convenience and decreased incidence and impact of Transdermal Therapy for OAB Advantages of Transdermal Therapy Not all drugs are easily absorbed through the skin but, for those that are or can be altered or enhanced to be so, transdermal delivery offers liver and gut wall metabolism. When oxybutynin is given as an immediate-release preparation, the ratio of plasma concentration of the parent compound to its metabolite N-desethyloxybutynin (DEO) is approximately 1:18, whereas the ratio when the compound is given transdermally is about 1:1 to 1:1.5.11 Based on the clinical behavior of the 2 preparations, it is believed that high levels of DEO may be responsible for many of the anticholinergic The consistent plasma levels provided by delivery via the transdermal route are particularly advantageous for drugs with short half-lives. distinct advantages.10 In addition to increasing convenience, transdermal delivery can change the metabolism and bioavailability of compounds and their metabolites and thus alter the therapeutic index of a particular drug. Because of the reduced frequency of administration, compliance should be enhanced with transdermal delivery. Most patches need to be changed once or twice per week. Delivery of drug via a transdermal route also avoids the hostile environment of the gastrointestinal tract, where drugs can be inactivated and absorption can vary depending on pH, food ingestion/interaction, and other local factors. In addition, some oral medications may cause nausea because of local effects, and some cannot be taken if the patient is already nauseated. Oral medications are subjected to first-pass metabolism in the liver. This can lead to breakdown of the parent compound into a less active or more toxic metabolite(s), drug-drug interactions (because there is competition for enzymatic pathways), or hepatic toxicity. Oxybutynin provides an example of how bioavailability can be altered by avoiding first-pass side effects, such as dry mouth and constipation. Another metabolic characteristic of transdermally delivered oxybutynin is that constant and consistent plasma levels are maintained. This has several advantages. For drugs that have a narrow therapeutic window (a small difference between the plasma level needed to achieve efficacy and that which causes toxicity), plasma levels can be more easily regulated to stay within that window. In addition, peak levels, which often occur with oral medications and are associated with toxicity and side effects, can be avoided. The consistent plasma levels provided by delivery via the transdermal route are particularly advantageous for drugs with short half-lives. The flip side of this is that drugs that require high plasma concentrations to achieve efficacy are not well suited for transdermal administration. Improving Transdermal Therapy for the Treatment of Overactive Bladder Oxybutynin Transdermal System The preceding article by David R. Staskin, MD, nicely explains the cur- rent state of transdermal therapy for OAB. The oxybutynin transdermal delivery system (TDS), which delivers 3.9 mg/d of oxybutynin via a transdermal patch, has been shown to have efficacy superior to placebo12,13 and similar to immediate-release oxybutynin and extended-release tolterodine, 4 mg once daily.13 Oxybutynin TDS has also demonstrated a significant reduction in the anticholinergic side effects that often lead to frustration and treatment discontinuation.11-13 The obvious questions that come to mind are whether higher doses of oxybutynin TDS will result in improved efficacy and whether these doses will alter the favorable side-effect profile of this therapy. Currently available data show that the ratio of oxybutynin to DEO remains consistent at dosages of 2.6 mg/d to 5.2 mg/d (Figure 1).11 In the dose-titration study reported by Davila and colleagues,11 dosages of oxybutynin were titrated to the induction of side effects (dry mouth) from 2.6 mg/d to 5.2 mg/d. Sixtyeight percent of patients reached the maximum dosage of 5.2 mg/d, suggesting that higher doses of transdermal oxybutynin should maintain the Figure 1. Increasing dosages of the oxybutynin transdermal delivery system show dose-dependent increases in plasma concentrations of oxybutynin and N-desethyloxybutynin (DEO). Between dosages of 2.6 mg/d and 5.2 mg/d, the ratio of oxybutynin to DEO stays about the same. Data from Davila GW et al. J Urol. 2001;166:140-145.11 50 Plasma Concentration (ng/mL) side effects. Reluctance to use transdermal therapy because of problems with patch technology, either conceptually or from a comfort/compliance standpoint, does not seem to be a problem. 40 2.6 mg/d 3.9 mg/d 5.2 mg/d 30 20 10 0 VOL. 5 SUPPL. 8 2003 Oxybutynin DEO REVIEWS IN UROLOGY S33 Transdermal Therapy for OAB continued Stratum corneum Figure 2. The structure of human skin. Living epidermis Dermal vasculature Eccrine gland duct current therapeutic index and may result in greater efficacy with maintenance of the favorable side-effect profile. A phase 4 dose-titration study in which patients will receive up to 7.8 mg/d of oxybutynin is currently under way and will help to answer the question of whether efficacy of the current transdermal preparation can be enhanced. Enhancing Transdermal Absorption The efficacy of transdermal therapy for OAB may be improved by altering the system to enhance the bioavailability (and thus reduce the size of the patch or application device) of oxybutynin or other compounds for the treatment of OAB. A reduction in adverse events related to transdermal delivery, particularly local skin reactions, and a better understanding of and ability to manage events will also help transdermal therapy gain acceptance. In order to appreciate the process of transdermal absorption, it is important to understand the structure of the skin. The skin consists of 2 layers: the avascular epidermis and the underlying, highly vascular dermis (Figure 2). Hair follicles and sweat glands, which arise in the dermis, S34 VOL. 5 SUPPL. 8 2003 traverse the epidermis and reach the skin surface. The epidermis itself consists of 2 layers: the stratum corneum, or horny layer, which acts as a protective membrane, and the living epidermis. The stratum corneum, which is relatively impenetrable, provides the available for transport. There are a number of ways to enhance transdermal absorption and increase drug bioavailability. These include modification of drug-vehicle interactions, the use of vesicles and particles to help transport drugs through the stratum corneum, modification or removal of the stratum corneum, bypassing the stratum corneum, and the use of energy-assisted methods.1 Certain characteristics (low molecular weight, solubility in oil and water, low melting point) make a compound ideal for crossing the skin barrier at a reasonable rate.1 It is also important that the partition coefficient of solute between the membrane and the bathing solution is sufficiently high to allow penetration of the stratum corneum. When a drug does not have suitable characteristics for penetration (eg, the partition coefficient is too low), a suitable prodrug can be used.1 The prodrug is then activated after The stratum corneum, which is relatively impenetrable, provides the rate-limiting step in transdermal delivery. rate-limiting step in transdermal delivery. It consists of a tight network of cells held together by a lipid bilayer analogous to a brick-andmortar structure.14 Drugs must penetrate the stratum corneum to the living epidermis, where metabolism can take place. Further transport into the dermis allows access to the rich supply of blood vessels and absorption into the circulation. Drugs may penetrate the stratum corneum by 1 of 3 routes: the intracellular route (through the lipid bilayer), which is the method most commonly employed; the transcellular route (directly through the corneocytes); or the transappendageal route (through hair follicles and sweat glands), which accounts for 0.1% of the surface area REVIEWS IN UROLOGY initial penetration. Other modifications of drug/vehicle interactions include chemical potential adjustment and ion pairing (of charged molecules with those of opposite charge). Liposomes and/or vesicles can be used to entrap drug molecules for easier transport though the lipid bilayer of the stratum corneum. The stratum corneum itself can be modified by hydration or through the use of chemical penetration enhancers, which improve penetration through lipid disruption, protein interaction, or partitioning promotion.15 The stratum corneum may be bypassed by enhancing appendageal transport or using techniques such as microneedle “injection,” in which hundreds of tiny needles are con- Transdermal Therapy for OAB tained within the delivery system.16 Techniques that remove or abrade the stratum corneum could potentially be used. Finally, a number of energy-assisted techniques to enhance permeation have been described, including the use of ultrasonography,17 radiofrequency,18 iontophoresis,19 and laser enhancement.20 Reducing and Treating Local Skin Reactions Transdermal delivery of certain drugs has the distinct advantage of reducing side effects because of steady-state serum concentrations and altered metabolism. However, this method of delivery has its own unique set of adverse events, which are primarily related to local skin reactions to the application device. A thorough understanding of these skin reactions can minimize their impact by enabling their prevention and treatment, as well as by allowing for improvement of the delivery system itself. Such improvements will have a major impact on the role of transdermal compounds in the future. Skin sensitivity reactions fall into 2 main categories: nonimmunologic and allergic. A recent review by Murphy and Carmichael21 provides a summary of these reactions. Nonimmunologic contact dermatitis, which is the most common skin reaction, includes irritant dermatitis, erythema, and burns. Irritant contact dermatitis involves an inflammatory reaction but no memory T-cell function and no involvement of antigen-specific immunoglobulins. The incidence of such reactions increases with the duration of occlusion. Erythema can occur as a result of vasodilatation characteristics of a particular drug, such as nitroglycerin or nicotine, or following removal of a transdermal system that contains a pressure adhesive. Such reactions are transient and resolve shortly after removal of the system. Burns have been reported in patients wearing nitroglycerin patches and are thought to be secondary to heating of the metallic component of the transdermal system by microwaves or defibrillation devices.22,23 Allergic contact sensitivity involves a cell-mediated immune response.21 In such cases, the risk of developing sensitization increases with prolonged use. Potential allergens include the adhesive, the membrane, the solvent, the enhancer, and the active drug. Allergic reactions are localized to the application site but may also occur at previous applica- tion sites. Allergic reactions can be delayed and may arise months after the initial application. Clinically, patients with skin reaction can present in a variety of ways with varying severity. Most reactions to oxybutynin TDS are mild and can be treated conservatively, with no need to discontinue the therapy. The most mild and most common (85%90%) reactions are nonimmunologic and resolve quickly and spontaneously. These reactions can be minimized with good skin care, moisturizers (but not immediately before patch application), and site rotation. Some patients (10%-15%) have periodic itching and/or redness during use of the patch that may persist for a few days after application. These cases can be managed as described above; if symptoms are bothersome, topical corticosteroids can be applied to the application site. Severe reactions, which occur in less than 1% of patients, are probably immunologically mediated. These reactions do not respond to topical corticosteroids and may be noted at prior application sites. Discontinuation of the transdermal therapy is recommended in such cases. In summary, skin reactions can be nonimmunologic local reactions or Main Points • The convenience and reduced side-effect profile associated with transdermal delivery of contraceptives, hormone replacement therapy, and pain medications have made this method of drug delivery more popular than oral therapy among many patients. • Delivery of oxybutynin via a transdermal route allows for consistent plasma drug levels and avoids potential inactivation/alteration in the gastrointestinal tract and first-pass metabolism in the liver. The resulting decrease in oxybutynin’s metabolite leads to fewer anticholinergic side effects compared with oral administration. • In an oxybutynin dose-titration study, 68% of patients reached the maximum dosage (5.2 mg/d), indicating that higher doses of transdermal oxybutynin may result in greater efficacy while maintaining the favorable side-effect profile. • Methods to enhance transdermal absorption and increase drug bioavailability, such as modification of drug/vehicle interactions, the use of vesicles and particles to help transport drugs through the stratum corneum, modification or bypass of the stratum corneum itself, and the use of energy-assisted methods, may lead to increased efficacy of transdermal therapy for overactive bladder. • Adverse events associated with transdermal therapy are primarily related to local skin reactions, which can be nonimmunologic or allergic and are most often mild to moderate in severity. VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S35 Transdermal Therapy for OAB continued allergic, immunologically mediated reactions. The vast majority of cases are mild or moderate in severity and can be treated conservatively. Severe allergic reactions require discontinuation of the patch. Understanding that mild reactions are not dangerous and are not necessarily related to an allergy to the medication or other component of the patch is important. Once that is established, patients can choose whether to continue using the system, depending on how bothersome the local skin reaction is. may help promote more widespread use of transdermal drug delivery as first-line therapy for OAB. References 1. 2. 3. 4. Current and Future Research It is important to establish whether the current formulation of oxybutynin TDS, when delivered at higher doses, will increase efficacy and maintain a favorable therapeutic index. Research is currently under way to make this determination. If this is the case, the development of a smaller, more convenient patch system, with enhanced bioavailability of oxybutynin, would seem to be the next logical step. In addition, improvements to the system itself can be made to reduce local skin reactions and improve adhesion. Transdermal delivery may also prove to be beneficial for future compounds for the treatment of OAB. Finally, studies that compare oral with transdermal OAB medications with respect to patient satisfaction and preference S36 VOL. 5 SUPPL. 8 2003 5. 6. 7. 8. 9. 10. 11. REVIEWS IN UROLOGY Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14:101-114. Ettinger B, Pressman A, Bradley C. Comparison of continuation of postmenopausal hormone replacement therapy: transdermal versus oral estrogen. Menopause. 1998;5:152-156. Lake Y, Pinnock S. Improved patient acceptability with a transdermal drug-in-adhesive oestradiol patch. Aust N Z J Obstet Gynaecol. 2000; 40:313-316. Ahmedzai S, Brooks DJ, for the TTS-Fentanyl Comparative Trial Group. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. J Pain Symptom Manage. 1997;13:254-261. Payne R, Mathias SD, Pasta DJ, et al. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol. 1998;16:1588-1593. Allan L, Hays H, Jensen N, et al. Randomized crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001;322:1154-1158. Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a ramdomized controlled trial. JAMA. 2001;285:2347-2354. Hedon B, Helmerhorst FM, Cronje HS, et al. Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch vs an oral contraceptive [abstract]. Int J Gynaecol Obstet. 2000;70(suppl 1):S78. Archer DF, Bigrigg A, Smallwood GH, et al. Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women. Fertil Steril. 2002;77(2 suppl 2):S27-S31. Ranade VV. Drug delivery systems. 6. Transdermal drug delivery. J Clin Pharmacol. 1991; 31:401-418. Davila GW, Daugherty CA, Sanders SW, for the Transdermal Oxybutynin Study Group. A shortterm, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol. 2001;166:140-145. 12. Dmochowski RR, Davila GW, Zinner NR, et al. Efficacy and safety of transdermal oxybutynin with urge and mixed urinary incontinence. J Urol. 2002;168:580-585. 13. Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62:237-242. 14. Barry W, Williams AC. Permeation enhancement through the skin. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology. Vol 11. New York: Marcel Dekker; 1995:449-493. 15. Mitragotri S. Synergestic effect of enhancers for transdermal drug delivery. Pharm Res. 2000; 17:1345-1359. 16. McAllister DV, Allen MG, Prausnitz MR. Microfabricated microneedles for gene and drug delivery. Annu Rev Biomed Eng. 2000;2:289-313. 17. Tachibana K, Tachibana S. The use of ultrasound for drug delivery. Echocardiography. 2001; 18:323-328. 18. Sintov AC, Krymberk I, Daniel D, et al. Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs. J Control Release. 2003;89:311-320. 19. Wong O. Iontophoresis: fundamentals. In: Hsieh DS, ed. Drug Permeation Enhancement: Theory and Applications. New York: Marcel Dekker; 1994:219-246. 20. Lee WR, Shen SC, Lai HH, et al. Transdermal drug delivery enhanced and controlled by erbium: YAG laser: a comparative study of lipophilic and hydrophilic drugs. J Control Release. 2001; 75:155-166. 21. Murphy M, Carmichael AJ. Transdermal drug delivery systems and skin sensitivity reactions: incidence and management. Am J Clin Dermatol. 2000;1:361-368. 22. Murray KB. Hazard of microwave ovens to transdermal delivery system. N Engl J Med. 1984;310:721. 23. Wrenn K. The hazards of defibrillation through nitroglycerin patches. Ann Emerg Med. 1990; 19:1327-1328.