Tadalafil as monotherapy and in combination regimens for the ...

463627TAR711753465812463627Therapeutic Advances in Respiratory DiseaseDU Udeoji and ER Schwarz

2012

Therapeutic Advances in Respiratory Disease

Review

Tadalafil as monotherapy and in combination

regimens for the treatment of pulmonary

arterial hypertension

Dioma U. Udeoji and Ernst R. Schwarz

Ther Adv Respir Dis

(2013) 7(1) 39 –49

DOI: 10.1177/

1753465812463627

© The Author(s), 2012.

Reprints and permissions:

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Abstract: The purpose of this review is to evaluate the use of tadalafil as monotherapy and in

combination regimens for the treatment of pulmonary arterial hypertension (PAH).

A systematic English language search of the medical literature using PubMed was

conducted between January 1960 and May 2012 using the search terms ‘tadalafil’,

‘therapy’, ‘pulmonary (arterial) hypertension’ and ‘combination therapy’. Special emphasis

was given to controlled clinical trials and case studies relevant for the use of tadalafil

in PAH. The search revealed 113 relevant publications, 31 of which were clinical trials,

52 were reviews and 12 were case reports. Of these, 12 were clinical studies in human

patients with PAH who were treated with tadalafil alone, and seven were clinical studies

in human patients with PAH who were treated with tadalafil in combination with other

agents. Only clinical studies in human patients were included. Exclusion criteria were

monotherapy other than using tadalafil and any combination therapy that excluded

tadalafil as part of the treatment regimen. Overall, 1353 human subjects were studied;

896 were treated with tadalafil alone while 457 subjects were treated with tadalafil

in coadministration. Tadalafil appears to be an effective and a safe treatment option

for patients with PAH. It improves clinical status, exercise capacity, hemodynamic

parameters, compliance issues and quality of life and reduces the occurrence of clinical

worsening. Tadalafil in combination therapy seems to be additive and synergistic in

relaxing pulmonary vascular muscle cells but more clinical trials on human subjects are

warranted.

Keywords: phosposdiesterase-5 inhibitor, pulmonary arterial hypertension, tadalafil

Introduction

Definition

Pulmonary hypertension (PH) is defined as an

increase in mean pulmonary arterial pressure

(mPAP) ≥25 mmHg at rest as measured by rightsided

cardiac catheterization.

The normal value for mPAP at rest is 14 ± 3

mmHg. Mean PAH of 20 mmHg is considered an

upper limit of normal but the significance of values

between 21 and 24 mmHg are not clear

[Badesch et al. 2009; Kovacs et al. 2009].

Classification of PH

The World Health Organization (WHO) has classified

PH into five diagnostic groups [Chin and Rubin,

2008; Galiè et al. 2011, McLaughlin et al. 2009]:

Group 1: pulmonary arterial hypertension (PAH),

which consists of (a) idiopathic PAH (IPAH),

(b) familial PAH (FPAH) (due to mutations in

the gene encoding for bone morphogenetic protein

receptor type II or BMPR2, for activinreceptor-like-kinase-1

gene or ALK1, or for

endoglin), (c) associated with connective tissue

Correspondence to:

Ernst R. Schwarz, MD,

PhD, FACC, FSCAI, FESC

Heart Institute of Southern

California, Beverly Hills,

Temecula, Los Angeles,

CA, USA and Cedars-

Sinai Medical Center, Los

Angeles, CA, USA

Ernst.schwarz@cshs.org

Dioma U. Udeoji, MD

Heart Institute of Southern

California, Beverly Hills,

Los Angeles, CA, USA and

Cedars Sinai Medical Center,

Los Angeles, CA, USA

diomaudeoji@yahoo.com

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Therapeutic Advances in Respiratory Disease 7 (1)

disorder (APAH) (congenital systemic to pulmonary

shunts, portal hypertension, HIV infection,

drugs and toxins) and others (thyroid disorders,

glycogen storage diseases, Gaucher’s

disease, hereditary hemorrhagic telangiectasia,

hemoglobinopathies, chronic myeloproliferative

disorders, splenectomy), (d) associated with significant

venous or capillary involvement (pulmonary

veno-occlusive disease [PVOD]), pulmonary

capillary hemangiomatosis (PCH), and (e) persistent

pulmonary hypertension of the newborn.

Group 2: pulmonary hypertension with left-sided

heart disease (left-sided atrial or ventricular heart

disease, left-sided valvular heart disease).

Group 3: pulmonary hypertension associated with

lung diseases and/or hypoxemia (chronic obstructive

pulmonary disease, interstitial lung disease,

sleep-disordered breathing, alveolar hypoventilation

disorders, chronic exposure to high altitude,

developmental abnormalities).

Group 4: pulmonary hypertension due to chronic

thrombotic and/or embolic disease (CTEPH)

thromboembolic obstruction of proximal pulmonary

arteries, thromboembolic obstruction of distal

pulmonary arteries, nonthrombotic pulmonary

embolism (tumor, parasites, foreign material).

Group 5: miscellaneous, including sarcoidosis,

histiocytosis X, lymphangiomatosis, and compression

of pulmonary vessels (adenopathy, tumor,

fibrosing mediastinitis) [Arif and Poon, 2011;

Chin and Rubin, 2008; Falk et al. 2010; Galiè

et al. 2011; McLaughlin et al. 2009; Sidorenko

et al. 2011].

PAH is a progressive and debilitating disease that

is characterized by restriction of flow of blood

through the pulmonary vasculature resulting in

progressive increase in mPAP in the presence

of normal pulmonary capillary wedge pressures

(

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DU Udeoji and ER Schwarz.

sclerodactyly, digital ulcers point towards scleroderma

while the presence of inspiratory crackles on

auscultation may point towards interstitial lung

disease as a cause) [Galiè et al. 2011].

Diagnosis of PAH

The diagnosis of PAH requires a comprehensive

evaluation including history and physical, chest

X-ray, pulmonary function testing, echocardiography,

often followed by connective tissue disease

serology, vasodilatory testing for reversibility and

tests to exclude thromboembolic disease as a contributing

factor [Chin and Rubin, 2008; Sidorenko

et al. 2011]. Once diagnostic evaluation has suggested

PAH, right-sided heart catheterization is

recommended to confirm the diagnosis and determine

the severity. In addition, left-sided heart disease

should be excluded as well as any correctable

cardiac problems such as left-to-right heart shunting.

Vasodilator testing can be performed during

the diagnostic procedure. The use of echocardiography

and magnetic resonance imaging (MRI)

also can be used to determine the prognosis [Arif

and Poon, 2011]. The New York Heart Association

(NYHA) functional classification system is used

to evaluate the functional status while the Medical

Outcomes Study Short Form 36-item questionnaire

(SF-36) is often used to monitor progress of

the disease. The exercise and functional capacity

can be assessed using cardiopulmonary exercise

testing or 6-min walk distance (6MWD) tests

[Arif and Poon, 2011]. A mPAP ≥25 mmHg at

rest or >30 mmHg with exercise and/or a pulmonary

capillary wedge pressure (PCWP) of ≤15

mmHg (without the presence of mitral stenosis)

and a mean PVR of ≥2 or 3 Wood units confirm

the diagnosis of PAH [Arif and Poon, 2011; Barst

et al. 2011; Buckley et al. 2010; Chin and Rubin,

2008; Falk et al. 2010; Frey and Lang, 2012; Katz,

2008; Liang et al. 2012; Naeije and Huez, 2007;

Sanchez et al. 2010].

Prostacyclic analogs: effects on

endothelial cells

Prostacyclin (or PGI 2 ) is released by the endothelial

cells and exerts its function through a paracrine

signal cascade that involves a G protein-coupled

receptor, termed prostacyclin receptor (or IP), on

endothelial cells and platelets. The endothelial

prostacyclin receptor becomes activated when it

binds to prostacyclin. This activation signals

adenyl cyclase to produce cyclic adenosine

monophosphate (cAMP) in the cytosol. cAMP

then activates protein kinase A (PKA). The activated

form of PKA continues to phosphorylate

and thereby inhibit myosin light-chain kinase,

leading to smooth muscle relaxation and

vasodilation.

There is dysregulation of the prostacyclin metabolic

pathways in patients with PAH as evidenced

by decreased prostacyclin synthase

expression in their pulmonary arteries and

decrease prostacyclin metabolites in their urine

[Galiè et al. 2011; McLaughlin et al. 2009].

Therapy with prostacyclic analogs causes

vasodilatation of the pulmonary vasculature as

well as improvements in the clinical signs and

symptoms and in the hemodynamic parameters

of patients with PAH.

Endothelin receptor antagonists

Endothelin-1 is a potent vasoconstrictor peptide

with mitogenic properties, which is overexpressed

in PAH [Affuso et al. 2010; McLaughlin et al.

2009]. Increased plasma levels of endothelin-1

correlate with the severity and prognosis of the

PAH [McLaughlin et al. 2009]. Endothelin-1

binds to endothelin receptors A and B [ET(A)

and ET(B)] to cause constriction of pulmonary

vasculature. By blocking this interaction,

endothelin receptor antagonists (ERAs) relax

pulmonary arterial smooth muscle and decrease

PVR.

Phosphodiesterase-5 inhibitors effect

on endothelial cells

Phosphodiesterase-5 (PDE-5) inhibitors act

through the nitric oxide (NO)-cyclic GMP pathway

to increase cGMP, which is the final mediator

in the NO-cyclic GMP pathway, and exert

vasodilatory and antiproliferative effects on pulmonary

vascular smooth muscles [Affuso et al.

2010; Klinger, 2011]. Sildenafil (Viagra TM , Pfizer,

USA; Revatio TM , Pfizer, USA) was the first studied

PDE-5 inhibitor and was approved in 1998 by

the US Food and Drug Administration (FDA) for

the treatment of erectile dysfunction. In 2005 it

was approved for the treatment of PAH based

on a large clinical trial [Galiè et al. 2005]. In

this trial, 278 patients with PAH were randomly

assigned to placebo or sildenafil (20 mg, 40 mg or

80 mg) for 12 weeks. The sildenafil treatment

group demonstrated significant improvements in

6MWD, hemodynamic parameters (mPAP) and

WHO functional class [Galiè et al. 2005].

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Therapeutic Advances in Respiratory Disease 7 (1)

Other approved PDE-5 inhibitors in the US are tadalafil

(Cialis TM , Eli Lilly, USA; Adcirca TM , Eli Lilly,

USA) and vardenafil (Levitra TM , GlaxoSmithKline,

USA; Staxyn TM , GlaxoSmithKline, USA). These

newer agents have potential advantages over sildenafil

such as a faster onset and longer duration of

action, higher selectivity for PDE-5, and increased

absorption [Rosenkranz et al. 2007; Sharma, 2007].

The three PDE-5 inhibitors also differ in the

pharmacokinetics of pulmonary vasorelaxation.

Tadalafil and sildenafil are selective for pulmonary

circulation, vardenafil has the most rapid effect

and sildenafil has a greater effect on arterial oxygenation

[Ghofrani et al. 2004]. Tadalafil has a

longer half-life (t 1/2 = 17.5 h) compared with sildenafil

(t 1/2 = 3-4h), and it is not associated with

visual side effects (blurring of vision and blue/

green color tinges) that might occur with sildenafil

use [Falk et al. 2010; Klinger, 2011; Levin

and White, 2011; Rosenzweig, 2010; Schwarz

et al. 2007; Sharma, 2007]. Tadalafil has a greater

affinity for PDE-5 when compared with other

PDE-5 inhibitors [Wrishko et al. 2008].

Tadalafil monotherapy

Tadalafil is a selective long-acting PDE-5 inhibitor

originally manufactured for the treatment of

erectile dysfunction and was approved by the FDA

in 2009 as a once-daily dose treatment for PAH

[Affuso et al. 2010; Croxtall and Lyseng-

Williamson, 2008; Falk et al. 2010; Frey and Lang,

2012; Galiè et al. 2009; Klinger, 2011; Rosenzweig,

2010]. In addition, to vasodilatory and antiproliferative

properties, tadalafil has anti-inflammatory

actions and antioxidant effects making it an effective

agent for the treatment of hypobaric hypoxiainduced

pulmonary hypertension [Rashid et al.

2012]. Tadalafil is mainly metabolized in the liver

by cytochrome P450 3A4 (CYP3A4) and coadministration

with other drugs that interfere with

cytochrome P450 can reduce the half-life and

hence the efficacy of the drug [Wrishko et al.

2008]. Tadalafil may cause transient decreases in

blood pressure. Coadministration with nitrates

should be avoided with all PDE-5 inhibitors (and

vice versa), and in the case of tadalafil, should be

avoided at least within 48 hours in order to avoid

potential life-threatening hypotension.

Tadalafil was approved as a once-daily dose of 40

mg taken orally with or without food [Frey and

Lang, 2012; Barst et al. 2011; Klinger, 2011;

Rosenkranz et al. 2007; Levin and White, 2011;

Rosenzweig, 2010]. It is convenient to use and is

considered to be safe and effective with minimal

side effects [Barst et al. 2011; Buckley et al. 2010;

Levin and White, 2011; Rosenzweig, 2010]. It has

shown to improve exercise capacity, hemodynamic

parameters, time to clinical worsening (relative risk

reduction = 68%, p = 0.038) and quality of life

(QoL) in patients with PAH [Galiè et al. 2009]

The first case of the successful use of tadalafil for

the treatment of a PAH patient was published in

2004 by Palmiera and colleagues [Palmiera et al.

2004]. The authors reported the use of 20 mg of

oral tadalafil in a 72-year-old female patient with

PAH who failed to respond to intravenous epoprostenol.

The patient showed significant improvements

in clinical status and hemodynamic

parameters. Since then there have been series of

case reports on the successful use of tadalafil to

treat patients suffering from PAH refractory to

other agents such as epoprostenol. In a case

series, 12 PAH patients with prior sildenafil use

demonstrated sustained improvement with the

use of tadalafil monotherapy [Tay et al. 2008]. A

study in 405 patients with PAH was the first placebo-controlled

trial using tadalafil with a favorable

safety profile [Galiè et al. 2009].

In a 16-week phase III (PHIRST) trial, 405

patients with PAH (idiopathic or associated), either

on background therapy with bosentan or treatment-naïve,

were randomized to placebo or 2.5,

10, 20 or 40 mg once daily of tadalafil. The study

showed a significant increase in 6MWD (from

33 m at baseline to 44 m at week 16, p < 0.01 for

treatment naïve patients receiving tadalafil 40 mg

once daily). Tadalafil 40 mg once daily dose also

delayed clinical worsening (p = 0.041), incidence

of clinical worsening (68% relative risk reduction;

p = 0.038), and QoL. There were no statistical significant

changes in WHO functional class. In

patients receiving bosentan 125 mg twice daily as a

background therapy the 6MWD was insignificantly

increased by only 23 m [Galiè et al. 2009].

Patients who completed the PHIRST trial could

still continue with the extended study (PHIRST

2) [Galiè et al. 2009]. In the 52-week, doubleblind,

uncontrolled PHIRST 2 trial, the longterm

safety and efficacy of tadalafil for treatment of

PAH were evaluated. The safety profile and adverse

events of tadalafil in PHIRST 2 and PHIRST trials

were the same. The 6MWD achieved in PHIRST

for the group of patients receiving tadalafil 20 mg

and 40 mg in both PHIRST and PHIRST 2 [406 ±

67 m (n = 52) and 413 ± 81 m (n = 59) at PHIRST

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DU Udeoji and ER Schwarz.

2 recruitment, respectively] were maintained at the

completion of PHIRST 2 [415 ± 80 m (n = 51)

and 410 ± 78 m (n = 59), respectively]. Few

patients on tadalafil 40 mg in PHIRST and

PHIRST 2 experienced WHO functional class

deterioration [6% (n = 5)] compared with patients

randomized to tadalafil 20 mg [9% (n = 7)] in

either trial. Both studies demonstrated that tadalafil

is a safe and effective treatment option for

patients with PAH and long-term treatment

appears to be sustained [Oudiz et al. 2012].

In a 4-week study on the efficacy and safety of

tadalafil compared with placebo in the treatment

of PAH, tadalafil was associated with improvements

in 6MWD (409.25 ± 40.25 m versus

319.37 ± 42.39 m, p < 0.0001), improvements in

Borg Dyspnea Index (BDI; 4.62 ± 2.56 versus

6.37 ± 2.61, p = 0.021), reduction in pulmonary

artery systolic pressure (PASP; 88.75 ± 23.26

mmHg versus 109.5 ± 23.78 mmHg, p < 0.0001),

and an improvement in the WHO functional class

[Bharani et al. 2007]. De Carvalho and colleagues

reported a case of a patient with IPAH (NYHA

class IV) who demonstrated improvement in

functional capacity and hemodynamic after treatment

with tadalafil [De Carvalho et al. 2006].

Tadalafil appears to have beneficial effects on

PAH irrespective of the underlying etiology

[Aggarwal et al. 2007]. A total of 13 PAH patients

with various comorbidities demonstrated improvements

in exercise tolerance (350.54 ± 255.06 s to

479.54 ± 195.00 s, p < 0.01) 4 weeks after addition

of tadalafil to their baseline medication.

Hemodynamics improved slightly but the differences

were not significant (mPAP 63.5 ± 26.2

mmHg versus 62.2 ± 24.8 mmHg, mean total

PVR 1858.6 ± 1138.9 dyne-sec.cm −5 versus

1737.3 ± 1017.2 dyne-sec.cm −5 , mean pulmonary

blood flow 3.26 ± 1.04 l/min versus 3.44 ±

1.26 l/min) [Aggarwal et al. 2007].

Tadalafil monotherapy has been shown to be a

safe and effective treatment option for the pediatric

population. A study to investigate the efficacy

and the safety of tadalafil in 33 pediatric patients

showed that 29 patients voluntarily switched from

sildenafil to tadalafil because of its once-daily

dosing. Furthermore, 14 of these patients demonstrated

improvements in hemodynamics (mPAP

53.2 ± 18.3 mmHg versus 47.4 ± 13.7 mmHg,

p < 0.05; PVR index 12.2 ± 7.0 versus 10.6 ± 7.2

dyne-sec.cm −5 /m 2 , p < 0.05) [Takatsuki et al.

2012]. This study concluded that tadalafil is a

safe treatment option for pediatric patients with

PAH and might reduce the progression of the illness

[Takatsuki et al. 2012].

Side effects of tadalafil

The most commonly reported side effects are

headache, back pain and myalgias, which occur

as a result of tadalafil affinity on PDE-5 [Arif and

Poon, 2011; Galiè et al. 2009; Sharma, 2007].

Other possible side effects are flushing, allergic

reactions, dyspepsia, migraine and rhinorrhea

(or stuffy nose) and these are usually transient.

Tadalafil in combination therapy

Oral medications, which target the three main

pathways involved in the pathophysiology of PAH,

namely the prostacyclic–cAMP pathway, the

endothelin pathway and the NO-cyclic GMP

pathway, are currently available (Table 1). These

oral medications are prostacyclic analogs, such as

epoprostenol (Flolan TM , GlaxoSmithKline, USA;

Veletri TM , Actelion, USA), treprostinil (Tyvaso TM ,

United Therapeutics, USA and Catalent Pharm

Solutions, USA, Remodulin TM ; Baxter Healthcare,

USA), iloprost (Ventavis TM ; Actelion, USA) and

beraprost (Berastolin; Taisho, Japan), endothelin

receptor antagonists such as ambrisentan

(Letairis TM , Gilead Sciences, USA) and bosentan

(Tracleer TM , Actelion, Pharmaceuticals, USA), as

well as PDE-5 inhibitors such as tadalafil (Cialis TM ,

Eli Lilly, USA; Adcirca TM , Eli Lilly, USA), sildenafil

(Viagra TM , Pfizer, USA; Revatio TM , Pfizer,

USA), and vardenafil (Levitra TM , GlaxoSmithKline,

USA; Staxyn TM , GlaxoSmithKline, USA)

[Anderson and Nawarskas, 2010; Affuso et al.

2010; Buckley et al. 2010; Liang et al. 2012; Maki

et al. 2011; Sidorenko et al. 2011].

Evidence-based guidelines recommend starting

treating PAH patients with monotherapy

[Anderson and Nawarskas, 2010; Barst et al.

2011]. The American College of Cardiology, the

American Heart Association, and the European

Society of Cardiology recommended starting IV

epoprotenol as first-line treatment for patients

with severe PAH (WHO functional class III and

IV) and sildenafil or ambrisentan or bosentan as

first-line treatment for patients with WHO functional

class III [Maki et al. 2011]. Intravenous epoprostenol

is highly efficacious but is expensive and

also difficult for patients to use [Anderson and

Nawarskas, 2010; Levin and White, 2011; Singh

et al. 2006]. Combination therapy is recommended

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Therapeutic Advances in Respiratory Disease 7 (1)

Table 1. FDA-approved agents for PAH.

Medications

Dosages and route of administration

PDE-5 inhibitors Sildenafil (Revatio TM , Viagra TM ) 20 mg orally TID or 10 mg IV bolus

TID

Tadalafil (Adcirca TM , Cialis TM )

40 mg orally once daily

ERAs Bosentan (Tracleer TM ) 62.5 mg orally BID for 4 weeks, then

125 mg orally BID for maintenance

Ambrisentan (Letairis TM )

5–10 mg orally once daily

Prostacyclic analogs Epoprostenol (Flolan TM , Veletri TM ) Start with 2 ng/kg/min IV and titrate

upwards with dose increment of 2ng/

kg/min every 15 min to clinical effect

Treprostinil

(Remodulin TM ,Tyvaso TM )

Start 1.25ng/kg/min IV or SQ, may be

reduced to 0.625 ng/kg/min, 18–54 µg

inhaled QID

Iloprost (Ventavis TM )

2.5–5 µg nebulized inhaled solution to

a maximum of 9 doses/day

A total of 11 medications had been approved by the FDA for the treatment of PAH.

PAH, pulmonary arterial hypertension; PDE-5, phosphodiestarase-5; ERA, endothelin receptor antagonist; BID, twice a

day; TID, three times a day; QID, four times a day; IV, intravenous injection; SQ, subcutaneous injection.

as second-line treatment for those patients who

do not respond to the initial treatment [Maki et al.

2011]. Many patients respond to single-drug

therapy [Tay et al. 2008] while others do not show

significant improvements [Badesch et al. 2007;

Barst et al. 2011; Galiè et al. 2004]. Some of the

patients who improved initially with monotherapy

do not sustain long-term success, which might

lead to the use of combination therapy [Barst

et al. 2011; Benza et al. 2007; Galiè et al. 2011;

Liang et al. 2012; Maki et al. 2011; Sidorenko

et al. 2011]. Combination treatment has been

advocated also for patients with 6MWD of less

than 380 m, signs of right-sided heart failure and

persistent functional class III or IV symptoms

refractory to treatment with one medication

[Chin and Rubin, 2008; Hoeper et al. 2005]. The

combination of these agents results in additive

and synergistic relaxation of the endothelincontracted

pulmonary ring, pulmonary remodeling,

and a delay of progression of the disease, as

well as improvement of clinical outcome, functional

capacity, hemodynamic parameters, and overall

prognosis [Affuso et al. 2010; Benza et al. 2007;

Buckley et al. 2010; Kiliçkesmez and Küçükoğlu,

2010; Liang et al. 2012; Maki et al. 2011]. Studies

have demonstrated significant improvements in

symptoms, hemodynamics, and the time to clinical

worsening with combination therapy [Chin

and Rubin, 2008; Hoeper et al. 2005].

Bendayan and colleagues combined tadalafil and

prostacyclins in four patients with PAH and

demonstrated that all symptoms and 6MWD

(from 214 to 272 m) were improved after 3

months [Bendayan et al. 2008]. Faruqi and colleagues

reported the use of tadalafil combined

with sitaxentan in three patients with IPAH

[Faruqi et al. 2010]. Sustained improvement in

exercise capacity and hemodynamic parameters

were noted and sustained without serious adverse

effects. In another report, a 49-year-old patient

with IPAH was treated with a combination of

bosentan, tadalafil, and beraprost with clinical

improvements and near-normal hemodynamics

at 6 months of therapy [Maki et al. 2011].

The combination of two or more drugs might

exert additive or synergistic effects [Barst et al.

2011; Liang et al. 2012]. Nowadays, the most

widely used combinations are endothelin receptors

blockers (bosentan) with PDE-5 inhibitors

(tadalafil, sildenafil) [Sidorenko et al. 2011; Liang

et al. 2012]. There is a possible pharmacokinetic

interaction between the two agents since tadalafil

is metabolized by CYP3A4, while bosentan

induces CYP3A4 and cytochrome P450 2C9

(CYP2C9) [Wrishko et al. 2008]. A study demonstrated

that after 10 days of coadministration,

bosentan reduced tadalafil exposure by 41.5%

with clinically irrelevant differences (

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DU Udeoji and ER Schwarz.

Table 2. Tadalafil as a monotherapy in the treatment of PAH (clinical studies).

# Study Design Number of

patients

Conclusion

1 Galiè et al. [2009] 16-week, double-blind,

placebo-controlled trial

2 Oudiz et al. [2012] 52-week, double-blind,

uncontrolled extended

study (PHIRST 2)

405 Tadalafil 40 mg, increased the time to clinical

worsening, incidence of clinical worsening and

QoL in this 16-week study.

357 The safety profile of tadalafil in PHIRST 2 and

PHIRST was the same and the improvements

in 6MWD demonstrated in the 16-week PHIRST

study appeared sustained for up to 52 additional

weeks of therapy in PHIRST 2.

3 Takatsuki et al. [2012] Retrospective study 33 Statistically significant different was observed

in terms of mPAP and PVR when pediatric

patients were switched from sildenafil to

tadalafil.

4 Ghofrani et al. [2004] Randomized

prospective study

60 PDE-5 inhibitors differ in their

pharmacokinetics of pulmonary vasodilation,

with tadalafil and sildenafil causing a significant

reduction in the pulmonary to systemic vascular

resistance ratio.

5 Aggarwal et al. [2007] Prospective study 13 When tadalafil was added to baseline treatment

of patients with PAH and other comorbidities,

there were improvements in effort tolerance,

and hemodynamic parameters after 4 weeks

of treatment irrespective of sex, age and

underlying etiology.

6 Bharani et al. [2007] Blinded crossover study 11 Tadalafil therapy led to significant

improvements in exercise capacity, BDI, WHO

functional Class and a reduction in PASP.

BDI, Borg Dyspnea Index; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PASP, echo-Doppler determined

pulmonary artery systolic pressure; PDE-5, phosphodiestarase-5; PVR, pulmonary vascular resistance; QoL, quality of life; 6MWD, 6-min walk

distance; WHO, World Health Organization.

Table 3. Tadalafil as a monotherapy in the treatment of PAH (case studies).

# Study Design Number of

patients

Conclusion

7 Tay et al. [2008] Case series 12 There was a sustained benefit of tadalafil

use in PAH patients with prior response to

traditional PDE-5 inhibitor (sildenafil).

8 Singh et al. [2006] Case series 2 Tadalafil was successfully administered to

two patients with severe PAH who could not

afford the cost of infusion prostacyclin.

9 De Carvalho et al. [2006] Case report 1 The use of long-acting PDE-5 inhibitor;

tadalafil improved the functional capacity and

the hemodynamics and may also improve

compliance.

10 Affuso et al. [2006] Case report 1 Tadalafil monotherapy improved exercise

capacity and quality of life in a middle aged

woman with idiopathic PAH after 6 months of

treatment.

11 Palmieri et al. [2004] Case report 1 Tadalafil, a long-acting PDE-5 inhibitor, may

be beneficial in treating patients with PAH

PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase-5.

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Therapeutic Advances in Respiratory Disease 7 (1)

Table 4. Tadalafil in combination regimens for the treatment of PAH (clinical studies).

# Study Design Number of

patients

Conclusion

12 Barst et al. [2011] 16-week, double-blind,

placebo-controlled trial

405 Tadalafil 40 mg, given orally was safe, increased

6MWD and provided clinical benefit in PAH

patients as monotherapy and when added to

bosentan but additional benefit could not be

concluded because of insufficient data.

13 Spence et al. [2009] Crossover study 26 Safety profile of tadalafil and ambrisentan

combination therapy was similar to that of either

agent alone.

14 Wrishko et al. [2008] Open-label randomized

study

15 Tadalafil alone and in combination with bosentan

were well tolerated but after 10 days of

coadministration, bosentan decreased tadalafil

exposure by 41.5% with clinically irrelevant

differences of less than 20% in bosentan

exposure.

15 Bendayan et al. [2008] Pilot study 4 Patients treated with combination therapy

of tadalafil and prostacyclin demonstrated

improvements in clinical symptoms, exercise

capacity and NYHA functional class after 3 months

of therapy.

NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; QoL, quality of life; 6MWD, 6-min walk distance.

Table 5. Tadalafil in combination regimens for the treatment of PAH (case studies).

# Study Design Number of

patients

Conclusion

16 Affuso et al. [2010] Case study 3 Long-term follow up of three patients with severe

idiopathic PAH who were treated with a combination of

tadalafil and sitaxentan, demonstrated improvements

in clinical condition, exercise capacity, functional class

and QoL with minimal adverse effect.

17 Faruqi et al. [2010] Case report 3 There was sustained symptomatic and hemodynamic

improvement in all three patients who received

tadalafil and sitaxentan combination treatment after

discontinuation of bosentan. No adverse effect related

to the combination treatment was noted.

18 Maki et al. [2011] Case study 1 Patient demonstrated progressive and sustained

improvement in clinical status. The hemodynamic

parameters returned close to normal range after 6

months of combination therapy with oral tadalafil,

bosentan, and beraprost.

PAH, pulmonary arterial hypertension; QoL, quality of life.

m; n = 37) for tadalafil in treatment-naïve patients

and 23 m (95% CI –2 to 48 m; n = 42) for tadalafil

coadministered with bosentan. Adverse

effects observed by the use of tadalafil in monotherapy

and in coadministration with bosentan

were identical [Barst et al. 2011].

The pharmacokinetic interaction between tadalafil

and ambrisentan were evaluated in a crossover

study of 26 healthy adults. In the presence of

tadalafil, ambrisentan maximum plasma concentration

was similar [105.0% (90% CI 95.9–

115.0%)], and systemic exposure was reduced

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DU Udeoji and ER Schwarz.

slightly [87.5% (90% CI 84.0–91.2%)], compared

with ambrisentan alone. The maximum

plasma concentration and systemic exposure of

tadalafil [100.6% (94.4–107.1%) versus 100.2%

(92.6–108.4%)] were the same in the presence

and absence of ambrisentan. The side effect profile

of the combination agents was similar to either

of the drugs alone [Spence et al. 2009]. Tadalafil

plus sitaxentan combination therapy has been

shown to improve QoL, exercise performance,

and outcome without serious adverse effects in

three patients with severe IPAH [Affuso et al.

2010].

Clinical study data review

Tables 2–5 summarize 10 clinical studies and

eight case reports involving human subjects.

Tadalafil monotherapy appears to be safe and

represents an effective treatment option for

patient with PAH [Barst et al. 2011; Buckley et al.

2010; Levin and White, 2011; Rosenzweig,

2010]. Several studies demonstrated that tadalafil

monotherapy improves exercise capacity,

hemodynamic parameters, the time to clinical

worsening, incidence of clinical worsening, and

QoL [Affuso et al. 2006, 2010; Arif and Poon,

2011; Barst et al. 2011; Buckley et al. 2010;

Croxtall and Lyseng-Williamson, 2010; Galiè et al.

2009; Levin and White, 2011; Pepke-Zaba et al.

2009; Sakuma and Shirato, 2008; Takatsuki

et al. 2012]. It is a convenient and cost-effective

treatment option for PAH.

Tadalafil in combination therapy demonstrated

to exert additive and synergistic effects in relaxing

pulmonary artery smooth muscles and in causing

pulmonary vascular muscle remodeling, which

eventually leads to slowing of the progression of

the disease and to improvements in clinical outcome,

functional capacity, hemodynamics, and

prognosis [Barst et al. 2011; Benza et al. 2007;

Liang et al. 2012; Levin and White, 2011; Maki

et al. 2011; Kiliçkesmez and Küçükoğlu, 2010]. It

has been advocated to start tadalafil coadministration

in patients with 6MWD of less than 380 m,

signs of right-sided heart failure, persistent functional

class III or IV symptoms refractory to treatment

with one medication, or those patients who

did not respond to the first-line therapy [Chin

and Rubin, 2008; Hoeper et al. 2005; Maki et al.

2011]. The availability of these different classes of

medications specific for treatment of patients

with PAH has improved the prognosis of this progressive

and debilitating disease.

Funding

This research received no specific grant from any

funding agency in the public, commercial, or notfor-profit

sectors.

Conflicts of Interest statement

The authors declare no conflicts of interest in

preparing this article.

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