Phosphodiesterase Inhibitors
Overview
Vasodilators such as prostacyclin analogues have been the mainstay therapy for pulmonary arterial hypertension for some time. Unfortunately, current agents are dogged by problems associated with drug delivery (e.g., injection-site pain), and in the case of currently marketed oral agents, there is a need for improved efficacy. Phosphodiesterase (PDE) inhibitors are also vasodilators. Sildenafil, which is approved for erectile dysfunction, is the most advanced agent in this class in development for pulmonary arterial hypertension. It has demonstrated both potency and a degree of pulmonary selectivity in initial clinical investigations. PDE inhibitors can be administered orally, a clear advantage to patients in terms of convenience.
In addition to sildenafil, several other PDE inhibitors are being researched for potential use in pulmonary arterial hypertension. Dong A Pharmaceuticals is conducting preclinical studies for its PDE-5 inhibitor, DA-8159. This compound is also in Phase II development for erectile dysfunction. Other agents under investigation for pulmonary arterial hypertension include Pfizer’s sildenafil analogue UK-343664, Tanabe’s PDE-5 inhibitor T-1032, and Altana’s PDE-3/4 inhibitor tolafentrine. Because of their early stage of development, these agents are not discussed in detail here.
If sildenafil (a PDE-5 inhibitor continues to demonstrate therapeutic potential in pulmonary arterial hypertension, it would create an opportunity for other already-commercialized PDE-5 inhibitors such as vardenafil (Bayer’s Levitra) and tadalafil (Lilly’s/Icos’s Cialis) to capitalize on the needs in the pulmonary arterial hypertension market that remain underserved. Both of these agents have longer half-lives than sildenafil, a characteristic that could translate to a more convenient once-daily dosing regimen. Thus far, clinical studies using sildenafil to treat pulmonary arterial hypertension have, on average, used a thrice-daily dosing schedule. It must be noted, however, that although both vardenafil and tadalafil are PDE-5 inhibitors, rigorous efficacy and safety studies will be necessary to guarantee approval for pulmonary arterial hypertension, assuming sildenafil itself gains marketing authorization for this indication. Furthermore, sildenafil has been granted orphan drug status in Europe for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH), a designation that could, in the near term, prevent the addition of pulmonary arterial hypertension to vardenafil’s and tadalafil’s labels.
Orphan drug exclusivity afforded to sildenafil in Europe extends to December 2013, although off-label use of available PDE inhibitors during this time cannot be discounted.
Mechanism Of Action
Of the family of PDE isozymes identified, types 1, 3, 4, and 5 are involved in controlling pulmonary arterial resistance. Under normal circumstances, PDE regulates the production of nitric oxide by metabolizing cyclic guanosine monophosphate (cGMP), the signaling molecule that promotes nitric oxide production. Inhibition of PDE in the lung yields higher cGMP concentrations in vascular smooth muscle, thereby enhancing nitric oxide activity and vasodilation and reducing pulmonary artery pressure. Inhibition of PDE-5 is also believed to reduce platelet aggregation action of nitric oxide and inhibit thrombus formation.
Sildenafil
Sildenafil (Pfizer’s Revatio) is a potent, selective inhibitor of PDE-5 that is approved for the treatment of erectile dysfunction. Under pressure from pulmonary hypertension patient support groups, Pfizer initiated Phase III trials in the United States and Europe for pulmonary arterial hypertension and submitted regulatory filings in the United States and Europe in November 2004. In January 2004, the European Medicines Agency granted sildenafil orphan drug status for pulmonary arterial hypertension and CTEPH. Data presented here focus primarily on the use of the drug for pulmonary arterial hypertension.
Sildenafil inhibits the enzyme PDE-5, an isoform that is abundant in the pulmonary vasculature and inactivates cGMP, a second messenger involved in nitric oxide-mediated vasodilation. Sildenafil promotes nitric oxide-induced pulmonary vasodilation in the lung by blocking catabolization of cGMP by PDE-5.
Many studies to date on the effectiveness of sildenafil in treating pulmonary arterial hypertension are limited by inconsistent trial design, small patient sample sizes, or the short-term administration of the agent. One nonrandomized trial evaluated the functional and symptomatic benefits of sildenafil therapy for five pulmonary arterial hypertension patients over a period of 12 weeks. Treatment (50 mg sildenafil twice daily) improved NYHA disease class in all patients and significantly increased the patients’ exercise capacity as measured by the six-minute walk distance (6MWD).
A randomized, double-blind, crossover study of 22 patients with idiopathic pulmonary arterial hypertension in NYHA class II or III compared sildenafil (25, 50, or 100 mg three times a day) with placebo for six weeks. Patients on sildenafil exhibited a 44% improvement in exercise tolerance, based on treadmill exercise times, and a reduction in both dyspnea and fatigue, based on patient-assessed quality of life (QoL) questionnaires. Patients did not suffer any major adverse effects.
Besides pulmonary arterial hypertension, sildenafil therapy has been shown to reduce pulmonary vascular resistance in patients suffering from human immunodeficiency virus-associated pulmonary arterial hypertension. Moreover, in an open-label trial involving 16 patients with pulmonary hypertension secondary to lung fibrosis, oral sildenafil (50 mg, n = 
compared favorably with infused epoprostenol (GlaxoSmithKline’s Flolan) (n = 8). At the conclusion of the study, patients demonstrated significant improvements in gas exchange and pulmonary vasodilation.
At the October 2004 meeting of the American College of Chest Physicians (ACCP), Pfizer unveiled the most recent data from a Phase III placebo-controlled multicenter trial. The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) study randomized 278 patients (mean age 49, 75% women) to placebo (n = 70) or to 20 mg (n = 69), 40 mg (n = 68), or 80 mg (n = 71) of sildenafil three times a day for 12 weeks. Of the total patient pool, 38% were NYHA functional class II and 58% class III. After 12 weeks, patients on the 80 mg dose demonstrated an increase in the 6MWD of up to 50 m, while those on 40 mg and 20 mg showed improvements in the 6MWD of 46 m and 45 m, respectively (p < 0.001). Overall, 35% of the sildenafil patient group improved by one functional class compared with 7% of the placebo group. The most common adverse event reported was headache (46 patients on sildenafil, 39 on placebo). Pfizer has extended the trial for patients on the 80 mg sildenafil dose; results are expected by mid to late 2005.
Several investigations have shown the synergistic benefit of adding sildenafil to an existing therapy, particularly prostacyclin analogues. In one study involving 73 patients on long-term inhaled iloprost (Schering AG/Cotherix’ s Ventavis), sildenafil was added to the regimen in 14 patients unresponsive to iloprost monotherapy. Adjunct sildenafil therapy after 9-12 months improved exercise capacity and pulmonary hemodynamics. A prior open-label, randomized trial, conducted by the same group, found that a regimen of sildenafil plus inhaled iloprost improved pulmonary vasodilation better than the administration of either agent alone. Another group of researchers published similar results, finding sildenafil increased iloprost’s vasodilatory effect. Numerous case reports have also identified favorable effects on pulmonary artery pressure when sildenafil is combined with inhaled nitric oxide, primarily in an acute setting.
Despite sildenafil’s potential benefit, the agent does pose a risk of adverse effects. Because it is not specific to the pulmonary circulation, it could trigger a systemic vasodilatory response, resulting in hypotension, headache, nausea, and syncope. In clinical studies assessing sildenafil’s efficacy for treating erectile dysfunction, researchers reported low levels of visual disturbance that correlated to the indirect inhibition of PDE-6 in the retina. However, in trials conducted so far in patients with pulmonary arterial hypertension, there have been no recorded cases of any serious side effects or drug interactions with agents such as digoxin (GlaxoSmithKline’s Lanoxin/Lanoxicaps, generics) and warfarin (Bristol-Myers Squibb’s Coumadin, Sanofi-Aventis’s Coumadine, generics).
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