DRUG PROFILE Tadalafil: a long-acting PDE5 inhibitor for the management of erectile dysfunction Allen D. Seftel, MD Erectile dysfunction is a significant medical condition affecting the total health of patients Associate Professor of Urology and their partners. Phosphodiesterase type 5 inhibitors treat erectile dysfunction by and Reproductive Biology, Case Western Reserve selectively inhibiting the nitric oxide–cyclic guanosine monophosphate pathway. Tadalafil University School of is a unique phosphodiesterase type 5 inhibitor that has a long period of responsiveness – Medicine, Cleveland, up to 36 h. Additionally, the absorption of tadalafil is not affected by a high-fat meal. OH, USA Tel.: +1 216 844 5504 These characteristics may give couples freedom in timing their sexual activity. Tadalafil is Fax: +1 216 844 1900 safe and effective for improving erectile function in both general and special populations. [email protected] The most common treatment-emergent adverse events are generally mild or moderate in severity and include headache, flushing or dyspepsia. Tadalafil may cause mild vasodilation; it should not be given concomitantly with organic nitrates or α-blockers, except for tamsulosin (0.4 mg once daily). Erectile dysfunction (ED), expected to affect [12,13] while sildenafil and vardenafil are associated some 322 million men worldwide by 2025 [1], is with a shorter period of responsiveness; as a conse- defined as the inability to achieve or sustain an quence, couples have a more limited window of erection sufficient to complete satisfactory sex- opportunity for sexual intercourse. ual intercourse [2]. ED is a significant medical Tadalafil is also unique in that the rate and condition affecting the total health of patients extent of its absorption are unaffected by con- and their partners and may also be a marker for sumption of high-fat food. Interactions with endothelial dysfunction and comorbid cardio- sildenafil and vardenafil and high-fat food may vascular disease, diabetes or depression [3]. In result in reductions and/or delays in drug addition, ED is undertreated – in a study of absorption [12]. men over 45 years of age, only 10% of sub- Other PDE5 inhibitors currently in develop- jects with sexual dysfunction reported seeking ment include FR229934 and TA-1790, availa- or receiving treatment [4]. ble in oral and transurethral forms. FR229934 Treatment options for ED are varied and his- is currently in the preclinical trial stages of torically, have ranged from counseling and life- development [14]. TA-1790 is a highly selective, style modification to vacuum constriction potent, orally active PDE5 inhibitor, believed to devices, intraurethral suppositories, surgical work faster than sildenafil to produce a maxi- implants and intracavernosal injectable prepara- mum increase in penile rigidity [101]. Thus far, tions such as alprostadil, papaverine and phen- preclinical data indicates that TA-1790, when tolamine [5]. The development of the combined with nitrates, causes a minimal drop phosphodiesterase (PDE) type 5 inhibitors has in blood pressure. A transurethral form is also brought a new era in ED treatment by giving being developed for men who cannot tolerate men the added option and convenience of oral the oral form [14]. Intranasal PT-141, a melano- medication. The PDE5 inhibitors have been cortin receptor agonist, has shown early promise Keywords: absorption, adverse shown to be safe and well tolerated in most as an effective and well-tolerated drug for man- events, erectile dysfunction, patient populations [6–8]. aging ED. In a recent study, the erectile half-life, long duration of response induced by PT-141 at a dose greater effectiveness, PDE5 inhibitors, pharmacokinetics, sildenafil, Overview of the market than 7 mg was statistically better than that tadalafil, vardenafil PDE5 inhibitors have been used globally since achieved by placebo. Erectile response increased 1998 [9], however, each of the PDE5 inhibitors – in a dose-dependent manner between 7 and sildenafil [9]; vardenafil [10] and most recently, 20 mg. Time-to-onset of first erection averaged tadalafil [11] – have distinctive characteristics based 30 mins after dosing. The drug was well toler- on molecular structure, enzyme inhibition profile ated; most common adverse effects were flush- and pharmacokinetic properties [12]. Tadalafil, for ing and nausea and there were no changes in Future Drugs Ltd example, has a long period of responsiveness vital signs or electrocardiogram parameters [15]. 10.1586/14750708.1.2.185 © 2004 Future Drugs Ltd ISSN 1475-0708 Therapy (2004) 1(2), 185–196 185 DRUG PROFILE – Seftel Figure 1. PDE5 inhibitors versus cGMP. period of responsiveness of tadalafil lasts for up to 36 h [9,13]. This may provide couples with greater flexibility in timing their sexual activ- Tadalafil cGMP O O ity. Tadalafil also differs from other PDE5 H CH HN N inhibitors in that its absorption is not affected N 3 H by high-fat food consumption [19]. Sildenafil or H N N N N 2 N H vardenafil may have diminished efficacy or O O OH delayed onset of action when taken with a meal [20,21]. Therefore, the unique pharmacody- O O O O namic advantages of tadalafil translate into P OH O important clinical benefits. Sildenafil Vardenafil O Chemistry O CH O NH 3 N Tadalafil’s empirical formula is C22H19N3O4 and CH2CH2O N N HN N N its chemical designation is N Pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, CH2CH2CH3 O S O 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahy- N dro-2-methyl-, (6R,12aR)-. Tadalafil is structur- O2S N ally distinct from sildenafil and vardenafil, which N N may account for the unique pharmacokinetic CH3 profile of the drug (Figure 1) [11]. Circled areas indicate the ring structures in sildenafil and vardenafil that resemble the purine moiety in cGMP. Although the structure of tadalafil is Pharmacodynamics different from sildenafil and vardenafil, all three agents have a high affinity Mechanism of action for the same catalytic site on the PDE5 enzyme. [Viagra® (sildenafil) prescribing Penile erection can be initiated through three information. Pfizer Inc, NY, USA (2002), Levitra® (vardenafil) prescribing information. Bayer major pathways, two of which cause formation Pharmaceuticals Corp., CT, USA (2003), Cialis® (tadalafil) prescribing information. Lilly ICOS of cyclic guanosine monophosphate (cyclic-3', 5' LLC, WA, USA (2003), Francis SH, Corbin JD. Molecular mechanism and pharmacokinetics of GMP), and the third of which causes the forma- phosphodiesterase-5. Curr. Urol. Rep. 4, 457–465 (2003).]. tion of cyclic adenosine monophosphate (cAMP). All three of these pathways are triggered Local therapies are available and, in certain by penile or sexual stimulation [22–24]. circumstances, are being used for the treatment The two cGMP pathways are the primary of ED. Currently on the market, MUSE® is a and the secondary. In the primary cGMP path- noninjectable, local transurethral delivery sys- way, visual or tactile sexual stimulation causes tem that can deliver a microsuppository of the release of acetylcholine (ACh) from the par- alprostadil directly to the urethra. Alprostadil is asympathetic nervous system, which in turn a vasodilator that, when given intraurethrally, innervates the nonadrenergic–noncholinergic increases blood flow to the penis and supports (NANC) nerves. NO is released by NANC erection. According to the manufacturer, onset neurons resulting in the activation of the of action is within 5 to 10 mins and the period enzyme guanylate cyclase, which in turn cata- of responsiveness is 30 to 60 mins [14,16]. lyzes the conversion of guanosine 5'-triphosphate Some investigators are exploring the possibility (GTP) to the neurotransmitter cGMP. cGMP of gene therapy, which could potentially restore then activates specific protein kinases that, physiologic erectile function, eliminating the need through phosphorylation, ultimately cause potas- for ‘on-demand’ medications. Avenues being sium channels to open and calcium channels to explored include the use of gene therapy with close. Intracellular calcium levels drop, smooth nitric oxide (NO) synthase, calcitonin–gene- muscle relaxes and the penis becomes erect [22–24]. related peptide, brain-derived neurotrophic factor In the secondary cGMP pathway, NO can also and vascular endothelial growth factor [17]. be released from the vascular endothelial cells. NO activates the enzyme guanylate cyclase, Introduction to the compound which catalyzes the conversion of GTP to cGMP. Tadalafil is the latest PDE5 inhibitor to be Accumulation of cGMP then triggers a cascade of introduced to the global market. Unlike silde- intracellular biochemical events that ultimately nafil and vardenafil, which have a short termi- leads to a decrease in intracellular calcium and nal half-life (4–5 h for sildenafil) [18], the relaxation of the penile smooth muscle. During 186 Therapy (2004) 1(2) Tadalafil – DRUG PROFILE this smooth muscle relaxation, the penile arteries on its low incidence of adverse events. For exam- dilate, resulting in blood flow into the corpus ple, tadalafil, with its low selectivity for PDE6 (dis- cavernosa. The penile veins become compressed, tributed in the retinal cells), may cause fewer visual trapping blood in the penis and producing an effects compared with sildenafil [12]. In tadalafil erection [22–24]. clinical trials, changes in color vision were reported In the cAMP pathway, the enzyme adenylate in less than 0.1% of subjects [11]. In clinical trials of cyclase catalyzes