Tadalafil: A Long-Acting Phosphodiesterase-5 Inhibitor for the Treatment of Pulmonary Arterial Hypertension

Abstract

Background

Tadalafil is a phosphodiesterase-5 (PDE-5) inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of pulmonary arterial hypertension (PAH).

Objective

The purpose of this review is to evaluate the pharmacology, pharmacokinetic properties, clinical efficacy, adverse effects, drug interactions, and dosage and administration of tadalafil in patients with PAH.

Methods

A literature search of MEDLINE and International Pharmaceutical Abstracts (1960 through September 5, 2010) was conducted with the search terms tadalafil, pulmonary arterial hypertension, and phosphodiesterase-5 inhibitor. Data found from orignial research and case series published in English were screened for relevancy to pharmacology, pharmacokinetics, clinical efficacy and safety, and tolerability. Relevant articles from the bibliographies of the identified published articles were also obtained. Unpublished data and posters were obtained from the manufacturer of tadalafil and the FDA Web site.

Results

By selectively inhibiting PDE-5, tadalafil causes nitric oxide–mediated vasodilation in the pulmonary vasculature. Tadalafil has a greater affinity (10,000-fold) for PDE-5 compared with the other PDE inhibitors and has a t_½ of 17.5 hours. In a controlled clinical study in patients with PAH, patients receiving tadalafil in a total daily dose of 40 mg had significant improvements in their 6-minute walk distance (33 m from baseline) and time to clinical worsening compared with those receiving placebo (both, P < 0.05). Tadalafil had adverse effects similar to placebo, with headache being the most commonly reported (42%).

Conclusions

In the small number of studies available, tadalafil was effective and well tolerated when used to treat patients with PAH. Compared with placebo, tadalafil was associated with significant improvements in exercise capacity and reduced time to clinical worsening (68% relative risk reduction; P = 0.038). There is limited evidence comparing tadalafil with sildenafil and vardenafil, and the studies are limited by short treatment durations.

Introduction

Pulmonary arterial hypertension (PAH), a subset of pulmonary hypertension (PH), encompasses a group of diseases characterized by restricted blood flow through the small pulmonary arteries, resulting in progressively elevated pulmonary artery pressure and pulmonary vascular resistance (PVR) that ultimately leads to right-sided heart failure and death. Although the pathogenesis is not well understood, multiple factors are believed to contribute to obstructive pathologic changes in the pulmonary circulation, resulting in impaired blood flow.1, 2, 3 Early on, endothelial dysfunction results in a reduced synthesis of endothelium-derived vasodilators (nitric oxide and prostacyclin) along with an overproduction of vasoconstrictors (endothelin-1 and thromboxane), which results in excessive vasoconstriction.³ Genetic loss-of-function mutations of bone morphogenetic protein receptor type 2 (BMPR2), viral infections, and ingestion of certain drugs (such as the anorexigens, dexfenfluramine, and aminorex) or toxins (toxic rapeseed oil) are all possible initial insults that trigger endothelial dysfunction.2, 3 As the disease progresses, alveolar hypoxia, inflammation, in situ thrombosis formation, and an imbalance between cell proliferation and apoptosis lead to vascular remodeling and further reductions in luminal cross-sectional area of pulmonary arteries and an increase in right ventricular afterload.²

The World Health Organization (WHO) has organized PH into 5 groups based on pathophysiologic mechanisms and clinical presentation, with PAH classified as group I.⁴ Patients at risk for the development of PAH include those with connective tissue disorders, portal hypertension, congenital heart disease, past exposure to appetite suppressants, HIV infection, hemoglobinopathies, and mutation in the BMPR2 gene, among others. This classification is distinct from WHO groups II through V, which describe PH to be associated with left-sided heart disease, hypoxia or lung disease, chronic thrombolic/embolic disease, or a miscellaneous cause such as sarcoidosis.

The diagnosis of PAH must be confirmed with a right heart catheterization—an invasive procedure used to obtain and measure certain hemodynamic parameters such as cardiac output, PVR, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP).5, 6 The current definition of PAH includes a mean pulmonary artery pressure (mPAP) >25 mm Hg at rest and a PCWP of ≤15 mm Hg.⁶ The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) also include a PVR >3 Wood units in their definition.⁵ Measurements obtained during this procedure may also help to predict prognosis. A prospective registry of PAH patients (N = 194) in the United States found that an increase in mPAP from <55 mm Hg to ≥85 mm Hg was associated with a decrease in median survival time from 48 months to 12 months (odds ratio [OR] = 1.16; 95% CI, 1.05–1.28), an increase in right atrial pressure (RAP) from <10 mm Hg to ≥20 mm Hg was associated with a decrease in median survival from 46 months to 1 month (OR = 1.99; 95% CI, 1.47–2.69), and an increase in cardiac index from <2.0 L/min/m² to ≥4.0 L/min/m² correlated with an increase in survival time from 17 months to 43 months (OR = 0.62; 95% CI, 0.46–0.82).⁷ Additionally, patients with an acute response (defined as a reduction in mPAP ≥10 mm Hg to reach an mPAP ≤40 mm Hg with either an increased or unchanged cardiac output) to a vasodilator, such as nitric oxide, are likely to show sustained benefits with long-term calcium channel blocker therapy.5, 7, 8

PAH is a very debilitating disease, and patients often experience exertional dyspnea, fatigue, and dizziness. As the disease progresses and right-sided heart failure develops, patients may have shortness of breath at rest, lower extremity edema, cyanosis, chest pain, palpitations, and syncope. The New York Heart Association (NYHA) functional classification system is used in PH to evaluate prognosis as well as patient response to interventions.⁹ Other monitoring tools include echocardiography, magnetic resonance imaging, and the Medical Outcomes Study 36-item short form questionnaire (SF-36). In order to objectively assess exercise capacity, a 6-minute walk distance (6MWD) test or cardiopulmonary exercise test (CPET) are typically used.10, 11

The prognosis of PAH is poor, with an estimated median survival in untreated patients of 2.8 years (95% CI, 1.9–3.7 years), and there is currently no cure for this fatal disease.⁷ However, there are many agents available that positively affect patient outcomes. Supportive therapy such as oxygen supplementation, warfarin anticoagulation, diuretics, and digoxin are used to manage symptoms and, in the case of warfarin, may improve survival.⁵ Calcium channel blockers are indicated in select patients with idiopathic PAH and who exhibit a positive acute vasodilator response during vasoreactivity testing.¹¹ In addition, there are targeted agents, many of which were developed in the last decade. Agents that work on specific pathways implicated in PAH include the prostanoids (epoprostenol, treprostinil, and iloprost), endothelin receptor antagonists (bosentan and ambrisentan), and the phosphodiesterase (PDE) inhibitors.⁵ Although these targeted therapies have been shown to improve symptoms, exercise capacity, functional class status, and, in the case epoprostenol, survival, their use may possibly be limited by toxicities, difficulty of administration, frequent dosing schedules, storage requirements, or the need for laboratory monitoring.

The first PDE-5 inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of PAH, sildenafil^⁎, was marketed in 2005. Since its approval, sildenafil has been widely used as first-line therapy for patients with NYHA functional class II or III PAH. This use is supported by both the ACCF/AHA and European Society of Cardiology treatment guidelines, which recommend either prostanoids, oral endothelin receptor antagonists, or oral PDE inhibitors in patients with mild (NYHA class II or III) PAH. Sildenafil use may benefit from its ease of administration and relatively less toxic side effect profile. Randomized, double-blind, placebo-controlled studies with this agent have reported improvements in exercise capacity (mean change in 6MWD of 51 m [95% CI, 41–60]¹² and increased treadmill exercise time of 211 [56] seconds [P < 0.0001]),¹³ hemodynamics (decrease in mPAP of 6.4 [1.1] mm Hg [P < 0.005] and decrease in mean PVR of 21.8 [3]% [P < 0.03]),¹⁴ WHO functional class (mean of 1.1 [0.08]; P = 0.0001),¹⁵ longer time to clinical worsening (P = 0.02, stratified log-rank test),¹⁶ and quality of life (improved physical functioning [13.71 vs 4.48; P < 0.001], general health [7.98 vs 0.31; P < 0.001], and vitality score [11.69 vs 5.5; P < 0.05] in the SF-36).¹⁷ Despite all these benefits, the short t_½ (∼4 hours) of sildenafil requires it to be administered 3 times a day; therefore, medication adherence is a concern. The difficulty of multiple daily dosing in PAH patients, who are likely to have other disease states that requiring additional medication, provides a significant barrier to optimizing a patient's treatment regimen. Tadalafil^† was approved in May 2009 for the treatment of PAH (WHO group I), making it the second agent in this class to be used for PAH in the United States.¹⁸