Ambrisentan

證據等級: L5

預測適應症: 10 個

Ambrisentan: From Pulmonary Arterial Hypertension to PAH Associated With Congenital Heart Disease

One-Sentence Summary

Ambrisentan is a selective endothelin type-A (ETA) receptor antagonist licensed internationally for pulmonary arterial hypertension (PAH), though it currently holds no MHRA marketing authorisation in the United Kingdom. The TxGNN model identifies multiple WHO Group 1 PAH subtypes as high-priority candidates; the most clinically actionable prediction is PAH associated with congenital heart disease (CHD-PAH), with a prediction score of 99.37%, supported by 9 clinical trials and 18 publications. Two further PAH subtypes — connective tissue disease-associated PAH (CTD-PAH) and HIV-associated PAH — independently reach L1 evidence with a “Proceed with Guardrails” recommendation, all sharing the same ET-1/ETA mechanistic rationale.

Quick Overview

Item	Content
Original Indication	Pulmonary Arterial Hypertension (idiopathic/heritable; licensed in US/EU but not currently MHRA-authorised)
Predicted New Indication	PAH Associated with Congenital Heart Disease (CHD-PAH / Eisenmenger Syndrome)
TxGNN Prediction Score	99.37%
Evidence Level	L1
UK Market Status	Not marketed
Number of MHRA Marketing Authorisations	0
Recommended Decision	Proceed with Guardrails

Why Is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack. Based on published literature, Ambrisentan is a highly selective oral ETA receptor antagonist. Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen that drives pulmonary arterial smooth muscle cell proliferation and progressive vascular remodelling. By selectively blocking ETA receptors while largely preserving ETB-mediated ET-1 clearance and endothelial prostacyclin release, Ambrisentan reduces pulmonary vascular resistance (PVR), lowers right ventricular afterload, and improves exercise capacity. This selectivity is thought to confer advantages over non-selective ERA agents in certain PAH subpopulations.

CHD-PAH — most severely expressed as Eisenmenger syndrome — belongs to WHO Group 1 PAH and shares the same core ET-1/ETA-driven pathobiology as idiopathic PAH. Chronic left-to-right cardiac shunting subjects the pulmonary vasculature to sustained excess pressure and flow, triggering endothelial dysfunction, ET-1 upregulation, and progressive arterial remodelling that is histologically indistinguishable from idiopathic PAH. ET-1 plasma levels are markedly elevated in Eisenmenger syndrome and correlate directly with disease severity and prognosis. The ESC/ERS 2022 PAH guidelines accordingly assign ERA therapy a Class I recommendation in Eisenmenger syndrome, confirming mechanistic coherence across Group 1 subtypes.

The clinical evidence directly supports this extrapolation. A prospective cohort study at Columbia University (Zuckerman et al., 2011, PMID 21371683) demonstrated haemodynamic and functional improvements specifically with Ambrisentan in Eisenmenger syndrome patients. A 2019 systematic review and meta-analysis (Li et al., PMID 31096477) confirmed the benefit of PAH-specific targeted therapy in ES. Additionally, Phase 3 Chinese PAH trial data (NCT01808313, n=134) — in which CHD-PAH constitutes a major subgroup — and long-term paediatric extension data (NCT01342952) provide further supportive evidence. The high TxGNN score therefore reflects genuine mechanistic and clinical plausibility.

Note on the top-ranked TxGNN prediction (Rank 1: Pulmonary Arteriovenous Malformation, score 99.41%): PAVM is primarily a structural anatomical abnormality treated by vascular embolisation rather than pharmacotherapy. The single case report identified (PMID 33969094) describes PAH arising as a complication of hereditary haemorrhagic telangiectasia (HHT), wherein ETA antagonism may address the PAH component but exerts no effect on the PAVM itself. This prediction is rated Hold (L4) and does not constitute a meaningful repurposing candidate; the CHD-PAH and CTD-PAH predictions are substantially more actionable.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT01808313	Phase 3	Completed	134	Open-label, single-arm, multicentre study in Chinese PAH patients; 12-week primary evaluation of Ambrisentan 5 mg on 6MWT; CHD-PAH is highly prevalent in Chinese PAH cohorts, making this a key direct efficacy data source
NCT01342952	Phase 2	Completed	38	Long-term open-label extension in paediatric PAH (ages 8–18); CHD is the leading cause of paediatric PAH; follow-up until age 18 or product approval, providing long-term safety and tolerability data in a CHD-predominant population
NCT01332331	Phase 2	Terminated	41	Randomised open-label dose-comparison (weight-adjusted high vs low dose) in paediatric PAH; terminated early, limiting statistical power, but supplies dose-exploration and safety data relevant to paediatric CHD-PAH prescribing
NCT01884675	Phase 3	Terminated	33	Randomised double-blind placebo-controlled study of Ambrisentan in inoperable CTEPH; terminated early — an important safety signal indicating that Ambrisentan is not appropriate for fibrotic lung disease or Group 3 PH
NCT01894022	Phase 3	Terminated	19	Open-label long-term extension of the CTEPH trial; terminated after parent study was discontinued; contributes limited long-term safety data
NCT04095286	Phase 1	Completed	29	Relative bioavailability crossover study comparing a lower-dose dispersible paediatric Ambrisentan formulation with the marketed tablet in healthy adults; supports development of age-appropriate dosing for paediatric CHD-PAH
NCT02688387	Phase 1	Completed	112	PK and relative bioavailability study of fixed-dose Ambrisentan + Tadalafil combination tablets; pharmacological foundation for the dual combination therapy used widely in CHD-PAH and Eisenmenger syndrome
NCT01383083	N/A	Unknown	42	Iloprost (not Ambrisentan) in adult Eisenmenger syndrome patients; provides comparative safety and efficacy context for the CHD-PAH treatment landscape
NCT00593905	N/A	Withdrawn	0	Pharmacogenomics study of ERA efficacy/toxicity in PAH; withdrawn before enrolment — no direct contribution to efficacy data

Literature Evidence

PMID	Year	Type	Journal	Key Findings
35412560	2022	Review	JAMA	Comprehensive review of PAH diagnosis and treatment; confirms ERAs (including Ambrisentan) as first-line therapy for WHO Group 1 PAH; PAH prevalence approximately 10.6 cases per million adults in the US
31096477	2019	Systematic Review / Meta-analysis	Medicine	Systematic review and meta-analysis of PAH-specific drug therapy in Eisenmenger syndrome; ERA and other PAH-targeted agents improve WHO functional class and exercise capacity in ES
21371683	2011	Prospective Clinical Study	Am J Cardiology	Ambrisentan in consecutive Eisenmenger syndrome patients at Columbia University (2007–2008); demonstrated improvements in resting and exercise haemodynamics and functional status — direct evidence specifically for CHD-PAH
34921523	2022	Clinical Study	Pediatric Pulmonology	Real-world safety and tolerability of Ambrisentan + Tadalafil combination in paediatric pulmonary hypertension; generally well tolerated, supporting combination use in paediatric CHD-PAH
41727855	2025	Review	Frontiers in Pediatrics	ET-1 pathobiology in failing Fontan circulation; directly demonstrates how ET-1 axis drives pulmonary vascular injury in complex single-ventricle CHD, reinforcing the mechanistic rationale for ETA antagonism
22104452	2011	Cohort / Registry	Postgraduate Medicine	Texas Adult Congenital Heart Program: characterises disease burden and treatment patterns in adults with CHD-PAH; underscores clinical need for targeted PAH therapy in this population
18333354	2007	Review	Romanian J Intern Med	Management of CHD-PAH including Eisenmenger syndrome; ERA therapy established as part of standard care, with approximately 30% of unrepaired shunt patients progressing to pulmonary vascular disease
28348949	2017	Case Report	Respir Med Case Reports	Adult Eisenmenger syndrome patient achieving meaningful clinical improvement with advanced PAH therapies including ERA; illustrates real-world benefit in a severe and historically undertreated condition
38447536	2024	Case Report	Kidney Blood Pressure Res	Cyanotic nephropathy as a systemic complication of Eisenmenger syndrome; highlights the importance of targeted PAH management to mitigate multi-organ consequences
41868707	2026	Case Series	Respir Med Case Reports	Sotatercept (activin signalling inhibitor) in severe refractory corrected complex CHD-PAH; illustrates the emerging role of combination and salvage strategies in CHD-PAH, and the unmet need in refractory disease

UK Market Information

Ambrisentan currently holds no MHRA marketing authorisation and is not listed as commercially available in the United Kingdom based on the data in this evidence pack (0 licences on record).

Note for UK clinicians: Ambrisentan is authorised by the European Medicines Agency as Volibris (5 mg and 10 mg film-coated tablets; originally GSK, later AstraZeneca) for WHO functional class II–III PAH. Post-Brexit, this EMA authorisation no longer automatically applies in Great Britain. Prescribers seeking access in the UK should consider:

MHRA Unlicensed Medicines (Specials) framework — named patient supply via a licensed Specials manufacturer or importer

‘Apply for a licence’ pathway — a formal MHRA marketing authorisation application, potentially via a reliance route based on the existing EMA approval

Existing NICE technology appraisals for the ERA drug class in PAH (refer to current BNF section 2.5.1.2, Pulmonary arterial hypertension, and relevant NICE guideline NG191 for PAH) — these may inform formulary decisions pending a formal licence

Any prescribing outside a marketing authorisation carries prescriber responsibility under General Medical Council guidance, and patients should be informed accordingly.

Safety Considerations

No UK-specific SmPC warnings, contraindications, or drug interaction data were available in this evidence pack.

Please refer to the European SmPC for Volibris (ambrisentan) and the BNF for complete prescribing information. Report suspected adverse reactions via the Yellow Card Scheme at yellowcard.mhra.gov.uk.

Key safety signals identified from clinical trial evidence within this pack:

Teratogenicity: ERA agents carry a serious teratogenicity risk (contraindicated in pregnancy, Pregnancy Prevention Programme required per EMA). This must be communicated to all women of childbearing potential prior to prescribing.
Hepatotoxicity: The ERA drug class is associated with aminotransferase elevations. The VOLT post-marketing registry (PMID 27282418, n=702) was specifically designed to characterise the incidence of LFT elevations >3× ULN. Baseline and regular hepatic function monitoring is required.
Contraindication in pulmonary fibrosis / Group 3 PH: The Phase 3 CTEPH trial (NCT01884675) was terminated early after safety signals emerged in patients with fibrotic lung disease. Ambrisentan must not be used in Group 3 PH (PH due to lung disease/hypoxia) or interstitial lung disease-associated PAH.
Fluid retention and oedema: ERA class effect; monitor carefully in CHD patients with compromised cardiac reserve or renal impairment.
Drug interaction — ciclosporin: Ciclosporin significantly elevates Ambrisentan plasma concentrations via P-glycoprotein inhibition; dose adjustment required. Relevant for post-transplant CHD patients.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: CHD-PAH and idiopathic PAH share the same ET-1/ETA-driven vascular pathobiology, and ERA therapy receives Class I recommendation (ESC/ERS 2022) for Eisenmenger syndrome. Direct prospective clinical data with Ambrisentan in Eisenmenger syndrome, Phase 3 trial data in Asian PAH cohorts with high CHD-PAH prevalence, and a supporting systematic review/meta-analysis collectively constitute L1 evidence. Ambrisentan is already EMA-authorised as Volibris, providing a clear regulatory precedent and reducing the evidentiary burden for UK access routes. Two further high-evidence indications — CTD-PAH (L1, 3 clinical trials, 19 publications, ARIES-1/2 and AMBITION subgroup data) and HIV-PAH (L1, Phase 3 RCT NCT00709956) — further strengthen the case for UK access across the PAH spectrum.

To proceed, the following is needed:

Confirm UK availability status: Verify whether Volibris retains a valid MHRA (or Great Britain) licence post-Brexit, or whether a fresh application or Specials route is required
Retrieve full SmPC safety data: Obtain MHRA/EMA SmPC including teratogenicity warnings, contraindication list (ILD, pregnancy), hepatotoxicity monitoring requirements, and complete drug interaction profile
Complete mechanistic dossier: Retrieve full DrugBank (DB06403) mechanism of action data to strengthen the regulatory-facing evidence pack
Define eligible patient population: CHD-PAH must be WHO Group 1 confirmed by right heart catheterisation; exclude patients with ILD, fibrotic lung disease, or Group 3 PH
Establish safety monitoring protocol: LFTs at baseline and monthly for the first 3 months, then quarterly; pregnancy test and contraception counselling before initiation
Explore NICE submission pathway: Current PAH appraisals (NG191) may require updating to include Ambrisentan specifically for CHD-PAH/Eisenmenger syndrome, particularly given there are currently no MHRA-licensed ERAs filling this UK gap
Consider registry enrolment: UK CHD-PAH patients initiated on Ambrisentan via Specials or compassionate use should be enrolled in a prospective registry (e.g., NHS Digital or BPH registry) to generate UK-specific real-world evidence
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.