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Abstract

The development of effective oral treatments that are capable of modulating the activity of endothelin receptor 1 (ET-1) represents a significant milestone in the field of pulmonary arterial hypertension (PAH). Randomized clinical trials confirm that endothelin receptor antagonist (ERA) treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression.

Ambrisentan is a propanoic acid-based ERA, showing preferential affinity for the type A ET-1 over the type B receptor. It provides another valuable, effective treatment option in PAH. Two large, randomized-placebo controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6 min walk distance. Additional secondary measures of improvement including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in clinical trials. A favorably low incidence of aminotransferase elevation indicating lower hepatic toxicity than other ERAs has been observed. Ambrisentan can be safely administered with warfarin or sildenafil without the need for dose adjustment of either therapy. A once daily oral medication with relatively few side effects is an attractive option, especially as the use of therapies in combination continues to increase. Long-term data and hemodynamic data confirm the benefits can be compared with other ERAs with fewer drug–drug interactions and a better liver safety profile.

Keywords

pulmonary arterial hypertension endothelin receptor antagonists ambrisentan

Background

Pulmonary arterial hypertension (PAH) is a severe disease characterized by a progressive increase in pulmonary pressure and resistance as a result of an abnormal narrowing of the precapillary pulmonary microvasculature leading to right heart failure. PAH is commonly diagnosed at a late stage of the disease and is associated with progressive clinical deterioration and premature death. The hemodynamic hallmark of PAH is a mean pulmonary arterial pressure (mPAP) of at least 25 mmHg with a pulmonary capillary wedge pressure of up to 15 mmHg, as measured at right heart catheterization [Galiè et al. 2009]. PAH prevalence ranges from 15 to 50 patients per million population [Humbert et al. 2006; Peacock et al. 2007]. Its pathogenesis is largely unknown. It is hypothesized that the interaction between genetic predisposition and environmental risk factors may be involved in the initial stages of the disease [Chan and Loscalzo, 2008; Hassoun et al. 2009]. Activation of anomalous repair mechanisms in response to endothelial damage has also been suggested as a key mechanism that leads to a diffuse progressively obliterative arteriopathy [Budhiraja et al. 2004].

There are currently three classes of drugs approved for the treatment of PAH: the endothelin receptor antagonists (ERAs) bosentan (Tracleer, Actelion Pharmaceuticals, Switzerland) and ambrisentan (Letairis, Gilead Sciences in the USA and Volibris, GlaxoSmithKline, UK in Europe), the phosphodiesterase 5 inhibitors (PDE-5i) sildenafil (Revatio, Pfizer, USA) and tadalafil (Adcirca, Lilly Ely, USA) and the prostacyclin analogues epoprostenol (Flolan, GlaxoSmithKline, USA), treprostinil (Remodulin, United therapeutics, UK) and iloprost (Ventavis, Actelion Pharmaceuticals, USA).

The human endothelin (ET) family consists of three 21-amino-acid isopeptides: ET-1, ET-2 and ET-3. Of these, only ET-1, first identified in 1988 [Yanagisawa et al. 1988], plays an important role, especially in the regulation of vascular tone, promoting endothelial dysfunction and vascular remodeling sustaining the PAH development. ET-1 is released principally from endothelial cells that line blood vessels, but also from other vascular and non-vascular cells.

Two receptor subtypes, types A and B (ETA and ETB), mediate the effects of ET-1 in vascular smooth muscle and endothelium. The main ETA-mediated actions are vasoconstriction and cell proliferation, while the primary actions mediated by ETB are antiproliferation, vasodilation and ET-1 clearance [Davenport et al. 1995; Galiè et al. 2004]. In patients with PAH, plasma ET-1 concentrations are increased about 10-fold and correspond with right atrial pressure (RAP) increase, disease severity and outcome [Rubens et al. 2001; Galiè et al. 1996]. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH [Galiè et al. 2004; Verhaar et al. 1998].

Drug profile

Ambrisentan, a propanoic acid based ERA, is a high-affinity (Ki = 0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor. The chemical structure of ambrisentan is (+)-(2S)-2-[(4,6dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. Although data describing the selectivity of ambrisentan for the ETA receptor vary between 29:1 [Bolli et al. 2004] and 4000:1 [Greene et al. 2006], depending on the assay cited, the drug is considered to be a highly selective ETA receptor antagonist [Gilead Sciences, 2011].

Various studies have confirmed that ambrisentan does not significantly affect the pharmacodynamics of concomitant medications for patients with PAH, as warfarin, sildenafil, tadalafil, ketonazole, noresthisterone 1 mg/ethinylestradiol 35 μg [Venitz et al. 2011].

The pharmacokinetics of ambrisentan have been well described in healthy volunteers and patients and appear to be approximately dose proportional in the clinical dose range. After oral administration, ambrisentan is rapidly absorbed with peak plasma concentrations occurring approximately 2 h post dosing in healthy individuals and in patients with PAH. The pharmacokinetics are linear and the steady state is reached after 4 days of repeated administration. The ambrisentan plasma elimination half life ranges from 13.6 to 16.5 h [Volibris product information, http://www.ema.europa.eu/docs/it_IT/document_library/EPAR_-_Product_Information/human/000839/WC500053065.pdf]. The overall bioavailability of ambrisentan is 80% and it is not affected by food. Ambrisentan is highly bound to plasma proteins (99%). Elimination is mostly through the biliary system with the majority of oral doses recovered in the urine and feces.

Studies on human liver tissue indicate that ambrisentan is metabolized primarily by uridine 5′-diphosphate glucuronosyltransferases 1A9S, 2B7S and 1A3S and, to a lesser extent, by cytochrome P450 3A (CYP3A) and CYP2C19. In vitro studies also suggest that ambrisentan is a substrate of organic anion transport protein and P-glycoprotein (P-gp) but not an inhibitor of P-gp. In vitro studies with human hepatocytes indicate that ambrisentan does not inhibit or induce phase I or II drug-metabolizing enzymes at clinically relevant concentrations [Buckley et al. 2011].

There are currently two therapeutic doses (5 and 10 mg daily) of ambrisentan approved for use in PAH. In the USA (Letairis), ambrisentan has been approved for patients with PAH with World Health Organization (WHO) functional class II or III symptoms to improve exercise capacity and delay clinical worsening. In Europe (Volibris), ambrisentan was approved in April 2008 following a positive opinion from the European Committee for Human Medicinal Products for the treatment of patients with PAH in functional class II and III to improve exercise capacity. Current guidelines [Galiè et al. 2009] suggest using ambrisentan in patients with PAH and WHO functional class II and III (recommendation I, level of evidence A). In WHO functional class IV the first-line drug is epoprostenol and the recommendation for ambrisentan is weaker (recommendation IIa, level of evidence C).

Clinical studies

The most significant studies on ambrisentan are reported in Tables 1 and 2.

Table 1.

Ambrisentan study characteristics: name, type of study, number of patients enrolled, PAH etiology, WHO functional class and duration.

Study	Type	Patients treated (n)	Etiology	WHO FC	Length of study
Badesh et al. [2012]	Open label, multicenter, single arm	224	IPAH and familial (31%) CTD (18%), chronic hypoxemia (22%), CTEPH (13%), other etiologies (16%)	II (29%) or III (65%)	24 weeks
Blalock et al. [2010]	Retrospective from one ARIES-1 center	12	IPAH (n=11), fenfen (n=1)	NA	2-year follow up
Cartin-Ceba et al. [2011]	Open label, observational, single center	13	Portopulmonary hypertension (100%)	II–III	390 days (median time)
D'Alto et al. [2012]	Prospective, single arm, open label	27	IPAH (n = 15), CHD-PAH (n = 7), CTD-PAH (n = 5)	NA	mean 2.8±0.4
Galiè et al. [2008]	Randomized controlled trial, placebo controlled	393	IPAH (64%), APAH (36%)	I/II (40%), II/IV (60%)	48 weeks
Klinger et al. [2011]	Post hoc RHC evaluation of ARIES patients	68	IPAH (65%)	I+II (25%), III+IV (75%)	median time from ambrisentan initiation to first follow up, RHC: 60 weeks
McGoon et al. [2009]	Multicenter, open label, single arm, phase II study	36	IPAH (63%), APAH (33%), FPAH (2%)	II (36%), III (63%)	12 weeks
Oudiz et al. [2009]	Extension study	383	IPAH (63%), APAH (37%)	I (3%), II (43%), III (46%), IV (8%)	2 years
Oudiz et al. [2011]	Integrated analysis of ARIES-1, -2, -E	383	See ARIES-E	See ARIES-E	3 years
Scott et al. [2010]	Open label observational	4	POPH with end-stage liver disease referent for transplant	NA	Evaluation before and after liver transplantation
Shapiro et al. [2012]	Open label efficacy and safety of combination therapy	33	NA	All FC III with suboptimal response to PDE5i	48 weeks
Yoshida et al. [2011]	Open label, extension study	21	IPAH (38%), FPAH (5%), CTD-PAH (19%), CHD-PAH (29%), POPH (10%)	II (67%), III (33%)	139 weeks
Zuckerman et al. [2011]	Retrospective, single center	17	Eisenmenger syndrome (100%)	NA	2, 5 ± 0.5 years

APAH, associated pulmonary arterial hypertension; CHD, congenital heart disease; CTD, connective tissue disease; CTEPH, chronic thromboembolic pulmonary hypertension; FC, functional class; FPAH, familial pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; NA, not applicable; POPH, portopulmonary hypertension; RHC, right heart catheterization; WHO, World Health Organization.

Table 2.

Ambrisentan studies endpoints (if applicable) and results or general outcome measure, patients on monotherapy during the study, causes of discontinuation and more frequent adverse events (and type).

Study	Primary endpoint	Results on primary endpoint or general outcome measure	Secondary endpoints	Results of secondary endpoint or general outcome measure	Survival/TTCW	Note
Badesch et al. [2012]	6MWD	6MWD increase (+21 m; 95% CI– 12–29) was observed at 24 weeks in the overall population compared with baseline	BNP WHO BDS	At week 24 compared with baseline: decrease in BNP (−26%; 95% CI −34 to −16%); WHO FC improvement in 23% of patients and deterioration in 7%; BDS decreases (−0.5%; 95% CI −0.8 to−0.3)	Survival 97% (95% CI 94–99%), freedom from clinical worsening 89% (95% CI 84−93%)	No 6MWD improvement for interstitial lung disease and COPD subgroups. 2 patients had ALT/AST elevation >8× ULN and discontinued therapy
Blalock et al. [2010]	NA	Improvements at 1 year in mPAP (p = 0.03), CO (p = 0.03), PVR (p < 0.01) improvement at 1 year of 6MWD maintained at 2 years	NA	Increase in RV ejection fraction from 29% at baseline to 46% at 2 years (p = 0.02)	NA	NA
Cartin-Ceba et al. [2011]	NA	mPAP decreased from a baseline median of 58 mmHg (37–63) to 41 mmHg (27–48) (p = 0.004) PVR median was reduced from 445 (329–834) to 174 dyne·s/cm^–5 (121–361) (p = 0.008)	NA	Statistically significant decrease of PVR after 1 year, maintained at 2 years	2 patients died	NA
D'Alto et al. [2012]	NA	After 12 months: significant improvements in 6MWD, WHO FC, proBNP, CI, PVR	NA	NA	Survival rate at 12 months: 93%; freedom from clinical worsening 85%	NA
Galiè et al. [2008]	6MWD	Significant improvement from baseline in 6MWD	BDS, WHO FC, SF-36	WHO FC (ARIES-1), QoL SF-36 score (ARIES-2), BDS (both studies), and BNP (both studies) were observed	Improvement in TTCW (ARIES-2)
Klinger et al. [2011]	NA	Significant decreases in mPAP and PVR and a significant increase in CI	N.A.	Mean right atrial pressure and pulmonary capillary wedge pressure were unchanged		PAP and PVR correlated with improvement in 6MWD
McGoon et al. [2009]	Incidence of ALT/AST>3× ULN	No patients experienced ALT/AST>3× ULN	Incidence of ALT/AST >5× ULN	No patients experienced ALT/AST >5× ULN	NA	NA
Oudiz et al. [2009]	6MWD	6MWD at 1 year (+25 m, +28 m and +37 m, for 2.5, 5 and 10 mg respectively), at 2 years for the 2, 5, 5 and 10 mg groups (+7 m +23 m and +28 m)	BDS FC	Improvement of BDS for 5 and 10 mg but not for 2.5 mg group, FC maintained or improved after 2 years	Survival: 94% (1 year) and 88% ( 2 years), TTCW 83% (1 year) and 72% ( 2 years)	1- and 2-year survival rates for IPAH: 96% and 89%; for CTD-PAH: 91% and 83%
Oudiz et al. [2011]	6MWD	After 2 and 3 years improvements compared to baseline were maintained in 5 and 10 mg dose group	BDS FC	Treatment effect was maintained with BDS over 3 years in 5 and 10 mg group	The Kaplan-Meier survival rate was 93% at 1 year (91–96%), 85% at 2 years (82–89%) and 79% at 3 years (75–83%).	Aminotransferase abnormalities of 1.6% per year
Scott et al. [2010]	NA	mPAP decreased to less than 35 mmHg prior to surgery	NA	6MWD: trend towards improvement after transplantation	NA	NA
Shapiro et al. [2012]	NA		NA	6MWD +15 m (95% CI −15 to 44), BDS −0.7, (95% CI −1.4 to +0.1), and NT-proBNP −35% (95% CI −53% to −10%)	At 48 weeks the Kaplan-Meier survival rate was 96% (95% CI 89–100%) and freedom from clinical worsening 80% (95% CI 66–94%)	97% of patients improved or maintained their WHO FC through 48 weeks
Yoshida et al. [2011]	Safety as defined per severity of AE	AEs related to the ambrisentan occurred in 11 patients (52%)	6MWD, WHO FC, BDS, plasma BNP level, mPAP, cardiac output, TTCW	Long-term administration of ambrisentan is well tolerated and is seen as having efficacious tendency for Japanese patients with PAH	NA	NA
Zuckerman et al. [2011]	NA	Statistically significant improvement was observed for mPAP (61.8 ± 8.5 mmHg at baseline versus 55.7 ± 4.6 mmHg at follow up, p = 0.05)	NA	Hemodynamic parameters remained stable	1 patient died of pulmonary embolism	Exercise capacity was maintained versus baseline (6MWD 395 ± 91 m at baseline versus 402 ± 70 m, p = 0.65) FC improvement in 3 patients, 1 patient worsened and 9 remained stable

6MWD, 6 min walking distance; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BDS, Borg dyspnea score; BNP, B-type natriuretic peptide; CI, confidence interval; CO, cardiac output; COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; FC, functional class; IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; NA, not applicable; NT-proBNP, N terminal pro B-type natriuretic peptide; QoL, quality of life; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; proBNP, pro B-type natriuretic peptide; PVR, pulmonary vascular resistance; RV, right ventricle; SF-36, Short Form 36; TTCW, time to clinical worsening; ULN, upper limit of normal; WHO, World Health Organization.

Randomized clinical trials and long-term extension

In two concurrent randomized, double-blind, placebo-controlled, multicenter, 12-week clinical trials in PAH (ARIES-1 and -2) [Galiè et al. 2008], ambrisentan was well tolerated, showed a good safety profile (associated with a low risk of aminotransferase abnormalities) and induced a significant improvement in WHO functional class, 6 min walking distance (6MWD), and time to clinical worsening relative to placebo. In particular, these studies randomized 392 patients with PAH to placebo or ambrisentan (ARIES-1: 5 or 10 mg; ARIES-2: 2.5 or 5 mg) orally once daily for 12 weeks. The majority of patients had idiopathic PAH (251/392, 64%), but a certain proportion of patients had associated PAH: connective tissue disease (CTD)-related (124, 32%), HIV-related (11, 2.5%) and anorexigen use-related (6, 1.5%) PAH. The majority of patients were in WHO functional class II (44%) or III (52%). The primary endpoint for each study was change in 6MWD from baseline to week 12. Clinical worsening, WHO functional class, Short Form-36 Health Survey score, Borg Dyspnea Score (BDS) and B-type natriuretic peptide (BNP) plasma concentrations were also assessed. The 6MWD increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (p = 0.008) and 51 m (p < 0.001) in ARIES-1 for 5 and 10 mg ambrisentan respectively, and 32 m (p = 0.022) and 59 m (p < 0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. The substantial overlap of 95% confidence intervals (CIs) for these data supports the conclusion that these results were not discordant. Moreover these studies had very similar patient populations; therefore, this difference may be due to random variability [Galiè et al. 2008].

Improvements in time to clinical worsening (ARIES-2), WHO functional class (ARIES-1), Short Form-36 score (ARIES-2), BDS and BNP (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations greater than three times the upper limit of normal (ULN). In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6MWD at 48 weeks was 39 m (95% CI 29–49 m).

A total of 383 patients completing either the ARIES-1 or -2 study were eligible to continue on ambrisentan for the ARIES-E extension study [Oudiz et al. 2009], designed to gather additional long-term safety and efficacy data. For the extension phase, those who had been initially randomized to placebo were randomized to 5 or 10 mg ambrisentan (ARIES-1) or ambrisentan 2.5 or 5 mg (ARIES-2), while patients on ambrisentan treatment continued at their current dose.

In this prospective analysis the authors observed sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH after 2 years of ambrisentan exposure.

In particular, the mean change from baseline in 6MWD was improved for the 5 mg (+23 m; 95% CI 9–38 m) and 10 mg (+28 m; 95% CI 11–45 m) groups.

The 3-year ambrisentan treatment was associated with a sustained improvement in exercise capability, dyspnea and WHO functional class for the 5 mg and 10 mg groups. For the combined dose group (2.5, 5, 10 mg), after 3 years of treatment, 64% (95% CI 58–69%) were free from clinical worsening, defined as death, lung transplantation, hospitalization for PAH, atrial septostomy, addition of prostanoid therapy or study withdrawal due to addition of other PAH therapy. The Kaplan–Meier survival rate at 3 years was 79% (95% CI 75–83%) for patients with PAH randomized to ambrisentan therapy [Oudiz et al. 2011].

In an open-label study performed in 25 Japanese adult patients with PAH who received ambrisentan 5 mg for the first 12 weeks and then 10 mg for an additional 12 weeks an improvement was observed in 6MWD, WHO functional class, BDS, BNP and cardiopulmonary hemodynamics [Yoshida et al. 2011].

More recently, ARIES-3 [Badesch et al. 2012], a long-term, open-label, multicenter, single-arm study, reconfirmed the results of previous placebo-controlled studies, demonstrating that ambrisentan is well tolerated and provides benefit in patients with PAH. A total of 224 patients with pulmonary hypertension due to idiopathic or familial PAH (31%), connective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were treated with ambrisentan 5 mg for 24 weeks and 53% of patients received stable background PAH therapies. The safety and tolerability of ambrisentan were similar to those seen in previous placebo-controlled PAH studies. After 24 weeks of therapy, an increase in 6MWD (+21 m; 95% CI 12–29) and a decrease in BNP (−26%; 95% CI 95% −34% to −16%) was observed in the overall population compared with baseline. However, an increase in 6MWD was not observed in the interstitial lung disease and chronic obstructive pulmonary disease subgroups. Appropriately, the authors concluded that larger, controlled studies are necessary to determine the efficacy and safety of ambrisentan in specific non group 1 pulmonary hypertension etiologies.

Effect on hemodynamics

The ARIES-1, -2, -3 and -E studies did not report hemodynamic data. A small retrospective study [Blalock et al. 2010] using right heart catheterization (RHC), magnetic resonance imaging (MRI) and 6MWD in 12 patients participating in the ARIES-1 trial showed improvements in hemodynamics and 6MWD at 3–5.5-year follow up. Conversely, cardiac MRI results were ambiguous, with only a significant increase in right ventricle ejection fraction. A second retrospective review [Klinger et al. 2011] in 68 patients enrolled in the ARIES-E study who underwent follow-up catheterization after at least 3 months (median time from initiation of ambrisentan therapy to first follow-up RHC 60 weeks, range 14–158) showed significant improvements in pulmonary hemodynamics. In patients receiving ambrisentan monotherapy (n = 58), mPAP decreased by 15%, cardiac index increased by 25% and pulmonary vascular resistance (PVR) decreased by 30%. No changes were observed in RAP and in capillary wedge pressure. A significant inverse correlation between change from baseline in 6MWD and change from baseline in PVR and mPAP (r = −0.43, p < 0.001; and r = −0.41, p < 0.001) was also observed. A weak inverse correlation was observed between change in 6MWD and change in mean RAP whereas no correlation was observed between change in 6MWD and change in cardiac index.

In an open-label, uncontrolled, dose-escalation study [Yoshida et al. 2011], 25 Japanese patients with PAH receiving 5 mg of ambrisentan once daily for the first 12 weeks and 10 mg once daily for an additional 12 weeks showed at 24 weeks a significant improvement in hemodynamics: mPAP −8.7 ± 13.9 mmHg (range −16.1 to −1.3); PVR −8.3 ± 7.6 mmHg/liter/min (range −12.4 to −4.3), RAP −0.7 ± 3.7 mmHg (range −2.7 to 1.3), cardiac index 0.63 ± 0.62 liters/min/m² (range 0.29–0.97), cardiac output 0.91 ± 0.89 liters/min (range 0.42–1.40).

The first and so far only prospective study evaluating hemodynamics using ambrisentan therapy in PAH is a long-term (12 ± 4 months of follow up), single-center, open-label, single-arm prospective study involving 27 consecutive adult patients with PAH [D’Alto et al. 2012]. The majority of patients had idiopathic PAH (n = 15), followed by coronary heart disease (CHD)-related PAH (n = 7) and CTD-related PAH (n = 5). At follow up, a significant improvement in clinical status (WHO functional class 2.5 ± 0.5 versus 2.8 ± 0.4; p = 0.0027), 6MWD (350 ± 62 versus 322 ± 66 m; p = 0.00005), pro B-type natriuretic peptide (pro-BNP) (392 ± 315 versus 588 ± 535 pg/ml; p = 0.008) and hemodynamics (cardiac index 2.7 ± 0.4 versus 2.4 ± 0.5 liters/min/m², p = 0.0001; PVR 8 ± 4 versus 10 ± 6 Wood Units, p = 0.007) was observed. In this study, the effect of ambrisentan on hemodynamics reinforces the clinical significance of the functional class, pro-BNP and exercise capacity improvements observed at 12 ± 4 months of treatment. No patient treated with ambrisentan developed aminotransferase concentrations more than three times the ULN. The results are consistent with previous retrospective hemodynamic data from Blalock and Klinger [Blalock et al. 2010; Klinger et al. 2011] and long-term efficacy and safety data from ARIES-E [Oudiz et al. 2009].

Associated pulmonary arterial hypertension (connective tissue diseases, congenital heart diseases, portopulmonary hypertension)

Apart from PAH associated with CTD, there are limited data on the efficacy and safety of oral ambrisentan in associated PAH. Although there has not been a study evaluating ambrisentan in CTD-related PAH, these patients were commonly enrolled in studies evaluating the safety and the efficacy of oral ambrisentan.

In the ARIES program [Oudiz et al. 2009] 124 patients (32%) had CTD-related PAH. Survival for the CTD-PAH cohort was 91% (95% CI 84–95%) at 1 year and 83% (95% CI 75–89%) at 2 years, and it was similar to the survival observed for the idiopathic PAH cohort, 96% (95% CI 92–98%) at 1 year and 89% (95% CI 84–93%) at 2 years.

A retrospective, single-center, open-label study [Zuckerman et al. 2011] evaluated short-term (mean 163 ± 57 days) and longer-term (mean 2.5±0.5 years) follow up of a cohort of 17 consecutive patients with Eisenmenger syndrome. At short-term follow up, there was an improvement in exercise capacity (6MWD 389 ± 74 versus 417 ± 77 m, p = 0.03, n = 11) and maintenance of rest SaO₂ (89% ± 7% versus 89% ± 6%, p = 0.75, n = 15), exercise SaO₂ (75% ± 15% versus 77% ± 15%, p = 0.33, n = 11), WHO functional class (improvement in two patients, no change in 13), and hemoglobin (16.5 ± 2.8 versus 15.8 ± 1.8 g/dl, p = 0.11, n = 14). At longer-term follow up compared with baseline and short-term follow up, there was stability of exercise capacity, SaO₂, WHO functional class and hemoglobin. The authors concluded that oral ambrisentan was safe and was associated with increasing exercise capacity at short-term follow up, with patients maintaining SaO₂, functional class and hemoglobin, and with no significant evidence of clinical deterioration at longer-term follow up. A potential limitation to the study was that most patients were previously treated with combinations of medications within the same class as ambrisentan (bosentan or sitaxentan). Although this may weaken the evaluation of effectiveness of ambrisentan, it should not affect the safety findings in this cohort. In addition, most patients were concurrently treated with other classes of PAH therapies.

Although oral ambrisentan is not licensed for portopulmonary hypertension (POPH) a small prospective, observational study has evaluated the hemodynamic responses and clinical outcomes of 13 consecutive adult patients with POPH who received monotherapy with ambrisentan (up to 10 mg daily) from January 2007 until December 2009 [Cartin-Ceba et al. 2011]. Patients were followed for a median of 613 days (interquartile range 385–1011). The mPAP decreased from 58 mmHg (range 37–63) to 41 mmHg (range 27–48) (p = 0.004) and PVR was reduced from 445 dyne·s/cm^–5 (range 329–834) to 174 dyne·s/cm^–5 (range 121–361) (p = 0.008). There was no difference in the longitudinal analysis of liver function tests (LFTs) [aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin and international normalized ratio] after 12 months of therapy. The authors concluded that in this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, ambrisentan monotherapy may significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function.

Combination therapy

Combination therapy is the standard of care for patients with PAH with unsatisfactory response to monotherapy in many PAH centers, although long-term safety and efficacy have not yet been fully explored [Galiè et al. 2009]. In fact as no one monotherapy has yet been shown to deliver satisfactory results in PAH, there is a strong clinical rationale for combination therapy, covering different pathways involved in the pathogenesis. Two recent meta-analyses showed that, compared with monotherapy, combination therapy for PAH significantly improves 6MWD and reduces the risk of clinical worsening [Bai et al. 2011; Zhu et al. 2012]. Nonetheless, no randomized, controlled trial (RCT) evaluating combination therapy with ambrisentan and PDE-5i or ambrisentan and prostanoids has been published so far.

ATHENA-1 [Oudiz et al. 2011], an open-label, multicenter study on ambrisentan and PDE-5i combination therapy in 33 patients with PAH with suboptimal response to a PDE-5i showed improvements in 6MWD (+18 m, p = 0.0437), BDS (−0.9; p = 0.0097) and N terminal pro B-type natriuretic peptide (NT-prpBNP) (−31%, p = 0.0216) at 24 weeks. At 48 weeks the improvements in 6MWD, BDS and NT-proBNP were maintained. At 48 weeks Kaplan–Meier survival was 96% (95% CI 89–100%) and freedom from clinical worsening (percentage event free) was 80% (95% CI 66–94%). Nearly all patients (97%) improved or maintained their WHO functional class through 48 weeks.

The role of combination therapy will be evaluated in the upcoming AMBITION trial [ClinicalTrials.gov identifier: NCT01178073]. This study is an international, event-driven (morbidity and mortality) clinical trial to compare two treatment strategies: first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in treating naïve patients with PAH.

Safety

The incidence of abnormal LFTs due to ambrisentan ranges from 0.8% to 3% [Galiè et al. 2008]. The risk of aminotransferase abnormalities after 3 years of ambrisentan treatment had an annualized incidence rate of 1.6%, a rate similar to placebo [Oudiz et al. 2011]. In a small group of patients in which treatment with either bosentan or sitaxentan was discontinued due to LFT abnormalities, ambrisentan at a dose of 5 mg was well tolerated [McGoon et al. 2009]. An increased incidence of peripheral edema has been reported with ambrisentan use.

In clinical trials ambrisentan was generally well tolerated with most adverse events being mild to moderate in intensity. In the 12-week ARIES-1 and -2 trials peripheral edema, headache and nasal congestion tended to be more frequent in patients treated with ambrisentan compared with placebo, but only nasal congestion appeared to increase with ambrisentan dose in both studies [Galiè et al. 2008]. The 2- and 3-year ambrisentan safety profile was similar to that seen in the ARIES-1 and -2 trials [Oudiz et al. 2009; 2011]. Adverse events that led to discontinuation of therapy were infrequent and were generally consistent with disease progression. Peripheral edema did not seem to limit treatment because most cases reported were mild to moderate and did not result in discontinuation of the study drug.

Liver toxicity is still considered the Achilles’ heel of ERA therapy [Hoeper, 2009]. In fact, a significant increase (more than three times the ULN) in serum aminotransferase concentrations represents a major side effect of ET-1 receptor antagonists. It appeared to be lower for patients treated with sitaxentan (3–5%) [Barst et al. 2006] compared with bosentan (11–12%) [Rubin et al. 2002], supporting possible differences among agents of this class of drugs. In most cases, liver injury is dose related and reversible with dose reduction or drug discontinuation, suggesting that hepatotoxicity is caused by a dose-dependent toxic effect. However, following serious cases of liver toxicity due to oral sitaxentan [Lavelle et al. 2009; Hoeper et al. 2009; Lee et al. 2011] Pfizer voluntarily withdrew sitaxentan from the worldwide market in December 2010 [European Medicines Agency, 2010].

The exact mechanisms by which ERAs cause liver injury are not clear. It has been suggested that ERAs [Hartman et al. 2010] or their metabolites competitively inhibit a bile salt transporter pump, leading to intracellular accumulation of bile salts, but other mechanisms cannot be excluded.

For ambrisentan, the incidence of abnormal LFTs range from 0.8% to 3%. Remarkably, in the ARIES-1 and -2 studies, no elevation in serum aminotransferase concentrations greater than three times the ULN was observed in the ambrisentan-treated patients to 12 weeks [Galiè et al. 2008].

In ARIES-3, six patients (2.7%) had ALT/AST elevations more than three times the ULN during the 24-week period. Two of these patients had ALT/AST elevations more than eight times the ULN and discontinued therapy [Badesch et al. 2012].

In the ARIES program, for the combined dose group (2.5, 5, 10 mg) the annualized risk of developing serum aminotransferase abnormalities (ALT/AST) more than three times the ULN was about 2% per year; most of these events were mild and did not lead to discontinuation of the drug. The risk of aminotransferase abnormalities after 3 years of ambrisentan treatment had an annualized incidence rate of 1.6%, a rate similar to placebo [Oudiz et al. 2011].

The Letairis Education and Access Program (LEAP) database collected data between 15 June 2007 and 14 December 2010 from 10,927 patients exposed to marketed ambrisentan in the USA with a total exposure representing 9893 patient/years. This database included 314 (2.87%) postmarketing spontaneous reports of possible hepatic injury, of which 156 (1.43%) were medically confirmed. A total of 79 (0.72%) of these medically confirmed cases met the criteria of clinically significant hepatic events [Ben-Yehuda et al. 2012].

Based on the LEAP data, in March 2011, the US Food and Drug Administration removed the requirement for mandatory monthly monitoring of LFTs with ambrisentan therapy; LFT monthly monitoring remains mandatory only in European countries. Monitoring during pregnancy and the black box warning against the use of ambrisentan in pregnancy was maintained.

McGoon and colleagues studied the feasibility of transition to oral ambrisentan in a small group of 36 patients who previously discontinued bosentan (n = 31), sitaxentan (n = 2) or both (n = 3) due to LFT abnormalities[McGoon et al. 2009]. No patient had an aminotransferase level greater than three times the ULN requiring ambrisentan discontinuation. One patient had a transient aminotransferase level greater than three times the ULN that resolved following a temporary dose reduction. No additional aminotransferase levels greater than three times the ULN were observed with long-term treatment (median exposure 102 weeks), despite dose increases to 10 mg daily in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments such as BDS and WHO functional class were observed. The authors concluded that ambrisentan treatment may be an option for patients who have discontinued bosentan or sitaxentan therapy due to LFT abnormalities.

In the RCTs ARIES-1 and -2 [Galiè et al. 2008] all ambrisentan doses were well tolerated, with most adverse events mild to moderate in severity (increased frequency of nasal congestion, peripheral edema and headache likely due to systemic vasodilatation, hemoglobin concentration reduction). The 3-year ambrisentan safety profile is consistent with that seen in the 2-year and 12-week data.

Drug–drug interaction

Bosentan is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2C9. Plasma concentrations of drugs metabolized by these isoenzymes will be reduced when coadministered with bosentan. Sitaxentan is an inhibitor of CYP2C9 and a weak inhibitor of CYP3A4/5, CYP2C19 and CYP2C8. It is metabolized by CYP2C9 and CYP3A4/5. Due to these characteristics, both drugs (bosentan and sitaxentan) have significant drug–drug interaction (DDI) [Galiè et al. 2009]. The results reported in prospective DDI studies can translate into meaningful and significant clinical implications for the selection of a therapeutic drug and dosing regimen [Venitz et al. 2011].

In contrast, ambrisentan DDI studies performed to date have revealed only one notable DDI that produced a significant increase in ambrisentan concentrations – namely, concomitant use of cyclosporine A (CsA) resulted in a twofold increase in ambrisentan exposure. However, as two therapeutic doses of ambrisentan are available with acceptable safety profiles, this twofold increase in exposure can be managed by limiting ambrisentan to the lower (5 mg) dose when coadministering with CsA [Spence et al. 2010]. No significant increase or decrease in CsA and antifungal azoles during concomitant ambrisentan administration has been reported, making it attractive for use in immunocompromised patients.

DDIs are an important issue for patients with PAH, potentially being the difference between efficacious and suboptimal therapy. For example, the reduced exposure to oral contraceptive drugs observed when administered in combination with bosentan is a serious concern as pregnancy is contraindicated in patients with PAH (increased risk of maternal death and potential for fetal teratogenicity) [Actelion Pharmaceuticals US, 2011]. Moreover, many patients with PAH, in particular those with idiopathic PAH, are on warfarin therapy. An open-label crossover study of 22 healthy volunteers receiving a single dose of racemic warfarin 25 mg alone and after 8 days of ambrisentan 10 mg daily showed that ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin [Walker et al. 2009]. As a consequence, significant dose adjustments of either drug are unlikely to be required in cases of coadministration.

Considering the low potential of ambrisentan for metabolic/drug transporter-mediated DDI with other drugs, as well as the low rate of liver toxicity observed in ambrisentan PAH trials [Bolli et al. 2004; Barst et al. 2006; Lavelle, 2009] it is unlikely that any potential risk of LFT abnormalities with ambrisentan would be increased due to greater ambrisentan exposure when coadministered with other drugs.

Conclusion

The development of effective oral treatments that are capable of modulating the activity of ET-1 represents a significant milestone in the field of PAH. Randomized clinical trials have confirmed that ERA treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression. Ambrisentan is an ERA showing preferential affinity for ETA over ETB. It provides another valuable, effective treatment option in PAH. Two large, randomized, placebo-controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6MWD. Additional secondary measures of improvement, including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in trials. Long-term data and hemodynamic data confirmed the benefits can be compared with other ERAs with fewer DDIs and a better liver safety profile.

There has been speculation as to whether selective ETA receptor antagonists could have greater clinical benefits than dual receptor. However, no conclusion can be drawn without any head-to-head clinical trials. Bosentan data have been collected in larger PAH populations. Moreover, the only randomized clinical trial on congenital heart disease related to PAH was of bosentan [Galiè et al. 2006]. Nevertheless, ambrisentan has some key features compared with bosentan: once-daily dosing compared with twice-daily dosing with bosentan, two approved efficacious doses, no need for titration, and only one relevant DDI with cyclosporine for the 10 mg dose. In addition, patients with elevation of liver enzymes during bosentan therapy could be switched to ambrisentan. As for bosentan, in a larger trial (ARTEMIS-IPF) ambrisentan failed to demonstrate efficacy in patients with idiopathic pulmonary fibrosis (IPF) with or without secondary pulmonary hypertension. Consequently, the manufacturer in agreement with the European Medicines Agency and other competent authorities updated the core labeling warning prescribers that ambrisentan is not recommended in patients with IPF with or without secondary pulmonary hypertension.

If the 3-year survival data for ambrisentan are encouraging, no one monotherapy has yet been shown to deliver satisfactory results on survival. The AMBITION study, which has time to clinical failure as the primary outcome measure, could provide the answer on the survival of patients with PAH receiving modern treatment.

Taking all the data together, we can conclude that oral ambrisentan has a favorable effect on exercise capacity, functional class, hemodynamics and clinical outcome in patients with PAH. A favorable efficacy-to-safety profile (very low elevation rate of serum aminotransferases) may offer potential advantages over current treatment strategies. Further larger studies and randomized clinical trials on specific subpopulations such as CHD- and CTD-related PAH are needed to test the safety and efficacy of ambrisentan in these scenarios.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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An update on the use of ambrisentan in pulmonary arterial hypertension

Abstract

Keywords

Background

Drug profile

Clinical studies

Randomized clinical trials and long-term extension

Effect on hemodynamics

Associated pulmonary arterial hypertension (connective tissue diseases, congenital heart diseases, portopulmonary hypertension)

Combination therapy

Safety

Drug–drug interaction

Conclusion

Footnotes

Funding

Conflict of interest statement

References