Identification
- Summary
Aprocitentan is an endothelin receptor antagonist used for the treatment of uncontrolled hypertension in patients inadequately controlled on other treatments.
- Generic Name
- Aprocitentan
- DrugBank Accession Number
- DB15059
- Background
Aprocitentan is a dual antagonist of endothelin receptors A and B used for treatment-resistant hypertension. It is the active metabolite of macitentan.
Approximately 10-15% of patients with hypertension have resistant hypertension, defined as uncontrolled high blood pressure despite the combined use of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses.1 Patients with resistant hypertension are at an increased risk of cardiovascular and renal events1 and have traditionally had limited additional treatment options. Endothelin receptor antagonism provides a novel therapeutic pathway for the management of patients with resistant hypertension.1,5
Aprocitentan was approved by the FDA in March 2024 for the treatment of hypertension in patients inadequately controlled with standard therapy.5 It was the first antihypertensive employing a novel mechanism to be approved in almost 40 years.5
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Aprocitentan (DB15059)
- Weight
- Average: 546.19
Monoisotopic: 543.9164 - Chemical Formula
- C16H14Br2N6O4S
- Synonyms
- Aprocitentan
- External IDs
- ACT-132577
Pharmacology
- Indication
Aprocitentan, in combination with other antihypertensive medications, is indicated to lower blood pressure in adult patients who are not adequately controlled on other therapies.6
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Hypertension •••••••••••• •••••• - Contraindications & Blackbox Warnings
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Aprocitentan exerts its pharmacologic effects by antagonizing receptors, ETA and ETB, which play a role in the pathogenesis of hypertension.6 In the PRECISION trial, aprocitentan demonstrated superiority to placebo in reducing both sitting systolic and diastolic blood pressures, with a mean reduction in sitting trough blood pressure of approximately 4 mmHg greater than placebo.6 Most of the antihypertensive effect of aprocitentan occurs within the first two weeks of treatment.6
Based on data from animal reproduction studies with other endothelin receptor antagonists, aprocitentan can cause fetal harm when administered during pregnancy. Prior to initiating treatment with aprocitentan, pregnancy should be excluded and acceptable contraceptive methods employed. Patients should monitor for pregnancy monthly and use effective contraception during treatment and for one month after discontinuation. Because of the significant risk of embryo-fetal toxicity, aprocitentan is only available through a restricted program called the Tryvio REMS.6
- Mechanism of action
Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system. It is produced constitutively by vascular endothelial cells to maintain vascular tone and is found in a variety of other cells including vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, neurons, and epithelial cells in the lungs and kidneys.1 ET-1 acts on two receptors, ETA and ETB, located on vascular smooth muscle cells and endothelial cells which serve to regulate blood pressure by inducing vasoconstriction or vasodilation. ET-1 is an extremely potent vasoconstrictor that works primarily via interactions with the ETA receptor and, under pathologic conditions, further induces vasoconstriction via interactions with ETB2.1 The overexpression of both ET-1 and ET receptors has been shown in a variety of pathologies, including essential hypertension, pulmonary arterial hypertension, chronic kidney disease, and diabetes mellitus.1
Aprocitentan is a dual endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors.6 This inhibition mitigates the hypertensive effects of ET-1 overexpression, including endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.6
Target Actions Organism AEndothelin-1 receptor antagonistHumans AEndothelin B receptor antagonistHumans - Absorption
The absolute oral bioavailability of aprocitentan is unknown.6 The mean Cmax and AUC0-tau following a single oral dose of 25mg are approximately 1.3 mcg/mL and 23 mcg.h/mL, respectively, with a Tmax between 4-5 hours.6
- Volume of distribution
The apparent volume of distribution of aprocitentan is approximately 20 L.6
- Protein binding
Aprocitentan is highly (>99%) protein-bound in plasma, primarily to albumin.6
- Metabolism
Aprocitentan is primarily metabolized by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis.6,4
- Route of elimination
Following the administration of a single radiolabeled dose of aprocitentan, approximately 52% of the dose was eliminated via urine (0.2% unchanged) and 25% via feces (6.8% unchanged).6
- Half-life
The effective half-life of aprocitentan is approximately 41 hours.6
- Clearance
The apparent clearance of aprocitentan is approximately 0.3 L/h.6
- Adverse Effects
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According to prescribing information, aprocitentan has been administered in single doses up to 600 mg, and as multiple doses of up to 100 mg daily, in healthy subjects (48- and 8-fold the recommended dose, respectively).6 Observed symptoms of overdosage included headache, nasal congestion, nausea, and upper respiratory tract infection. In the event of an overdose, standard supportive treatment should be employed as clinically indicated. As aprocitentan is highly protein-bound, dialysis is unlikely to be effective.6
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAdenine The metabolism of Aprocitentan can be decreased when combined with Adenine. Amitriptyline The metabolism of Aprocitentan can be decreased when combined with Amitriptyline. Asciminib The metabolism of Aprocitentan can be decreased when combined with Asciminib. Atazanavir The metabolism of Aprocitentan can be decreased when combined with Atazanavir. Cannabidiol The metabolism of Aprocitentan can be decreased when combined with Cannabidiol. - Food Interactions
- Take with or without food. Co-administration with food does not appear to alter the pharmacokinetics of aprocitentan to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tryvio Tablet, film coated 12.5 mg/1 Oral Idorsia Pharmaceuticals Ltd 2024-03-20 Not applicable US 
Categories
- Drug Categories
- Amides
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- BSEP/ABCB11 Inhibitors
- Cytochrome P-450 CYP2C18 Inhibitors
- Cytochrome P-450 CYP2C18 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Endothelin Receptor Antagonists
- P-glycoprotein substrates
- Sulfones
- Sulfur Compounds
- UGT1A1 Inhibitors
- UGT1A1 Substrates
- UGT2B7 Inhibitors
- UGT2B7 substrates
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- MZI81HV01P
- CAS number
- 1103522-45-7
- InChI Key
- DKULOVKANLVDEA-UHFFFAOYSA-N
- InChI
- InChI=1S/C16H14Br2N6O4S/c17-11-3-1-10(2-4-11)13-14(24-29(19,25)26)22-9-23-15(13)27-5-6-28-16-20-7-12(18)8-21-16/h1-4,7-9H,5-6H2,(H2,19,25,26)(H,22,23,24)
- IUPAC Name
- N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]aminosulfonamide
- SMILES
- NS(=O)(=O)NC1=C(C(OCCOC2=NC=C(Br)C=N2)=NC=N1)C1=CC=C(Br)C=C1
References
- Synthesis Reference
Martin Bolli, Christoph Boss, Alexander Treiber. " 4-pyrimidinesulfamide derivative ", US Patent US8324232B2.
- General References
- Heidari Nejad S, Azzam O, Schlaich MP: Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Curr Hypertens Rep. 2023 Oct;25(10):343-352. doi: 10.1007/s11906-023-01259-z. Epub 2023 Aug 11. [Article]
- Clozel M: Aprocitentan and the endothelin system in resistant hypertension. Can J Physiol Pharmacol. 2022 Jul 1;100(7):573-583. doi: 10.1139/cjpp-2022-0010. Epub 2022 Apr 3. [Article]
- Fontes MSC, Dingemanse J, Halabi A, Tomaszewska-Kiecana M, Sidharta PN: Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment. Sci Rep. 2022 Nov 9;12(1):19067. doi: 10.1038/s41598-022-22470-z. [Article]
- Sidharta PN, Fischer H, Dingemanse J: Absorption, Distribution, Metabolism, and Excretion of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Humans. Curr Drug Metab. 2021;22(5):399-410. doi: 10.2174/1389200222666210204202815. [Article]
- American Journal of Managed Care: FDA Approves Idorsia's Tryvio for Resistant Hypertension [Link]
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- External Links
- ChemSpider
- 25027753
- BindingDB
- 50395672
- ChEBI
- 76609
- ChEMBL
- CHEMBL2165326
- ZINC
- ZINC000095553608
- Wikipedia
- Aprocitentan
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Resistant Hypertension 1 3 Withdrawn Treatment Hypertension / Renal Insufficiency,Chronic 1 2 Completed Treatment Hypertension, Essential Hypertension 1 1 Completed Other Healthy Volunteers (HV) 7 1 Completed Other Healthy Volunteers (HV) / Hepatic Impairment 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 12.5 mg/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.014 mg/mL ALOGPS logP 2.85 ALOGPS logP 2.58 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 7.79 Chemaxon pKa (Strongest Basic) 3.26 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 142.21 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 112.81 m3·mol-1 Chemaxon Polarizability 44.36 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Phosphatidylinositol phospholipase c activity
- Specific Function
- Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is:...
- Gene Name
- EDNRA
- Uniprot ID
- P25101
- Uniprot Name
- Endothelin-1 receptor
- Molecular Weight
- 48721.76 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Peptide hormone binding
- Specific Function
- Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
- Gene Name
- EDNRB
- Uniprot ID
- P24530
- Uniprot Name
- Endothelin B receptor
- Molecular Weight
- 49643.255 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Steroid binding
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1-1
- Molecular Weight
- 59590.91 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Glucuronosyltransferase activity
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60694.12 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C18
- Uniprot ID
- P33260
- Uniprot Name
- Cytochrome P450 2C18
- Molecular Weight
- 55710.075 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Transporter activity
- Specific Function
- Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Virus receptor activity
- Specific Function
- The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presenc...
- Gene Name
- SLC10A1
- Uniprot ID
- Q14973
- Uniprot Name
- Sodium/bile acid cotransporter
- Molecular Weight
- 38118.64 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Drug created at May 20, 2019 14:46 / Updated at March 29, 2024 06:25