Aprocitentan

Identification

Summary

Aprocitentan is an endothelin receptor antagonist used for the treatment of uncontrolled hypertension in patients inadequately controlled on other treatments.

Brand Names
Tryvio
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
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

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatHypertension••••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

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

TargetActionsOrganism
AEndothelin-1 receptor
antagonist
Humans
AEndothelin B receptor
antagonist
Humans
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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

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.
DrugInteraction
AbaloparatideAbaloparatide may increase the hypotensive activities of Aprocitentan.
AcebutololAcebutolol may increase the hypotensive activities of Aprocitentan.
AceclofenacThe therapeutic efficacy of Aprocitentan can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Aprocitentan can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidAcetylsalicylic acid may decrease the antihypertensive activities of Aprocitentan.
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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TryvioTablet, film coated12.5 mg/1OralIdorsia Pharmaceuticals Ltd2024-03-20Not applicableUS flag
TryvioTablet, film coated12.5 mg/1OralIdorsia Pharmaceuticals Ltd2024-03-20Not applicableUS flag

Categories

ATC Codes
C02KN01 — Aprocitentan
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. American Journal of Managed Care: FDA Approves Idorsia's Tryvio for Resistant Hypertension [Link]
  6. FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
ChemSpider
25027753
BindingDB
50395672
RxNav
2679059
ChEBI
76609
ChEMBL
CHEMBL2165326
ZINC
ZINC000095553608
Wikipedia
Aprocitentan

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3CompletedTreatmentResistant Hypertension1somestatusstop reasonjust information to hide
3WithdrawnTreatmentHypertension / Renal Insufficiency,Chronic1somestatusstop reasonjust information to hide
2CompletedTreatmentHypertension, Essential Hypertension1somestatusstop reasonjust information to hide
1CompletedOtherHealthy Volunteers (HV)7somestatusstop reasonjust information to hide
1CompletedOtherHealthy Volunteers (HV) / Hepatic Impairment1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral12.5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11787782No2018-03-022038-03-02US flag
US11680058No2018-07-262038-07-26US flag
US11174247No2017-11-062037-11-06US flag
US8324232No2009-09-212029-09-21US flag
US10919881No2018-02-262038-02-26US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.014 mg/mLALOGPS
logP2.85ALOGPS
logP2.58Chemaxon
logS-4.6ALOGPS
pKa (Strongest Acidic)7.79Chemaxon
pKa (Strongest Basic)3.26Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area142.21 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity112.81 m3·mol-1Chemaxon
Polarizability44.36 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0001090000-8f292d4ef95b00d53ebd
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9233010000-dc0b967b77a0e2d90b38
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-3338980000-557c12d61ea49802632d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004l-9115000000-2d075e7479fd3aa652c2
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014l-0094720000-8045a327f241edb26eb9
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9011000000-4ad997934dd24b15132d
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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
  1. 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
  1. FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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
  1. 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
  1. 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