NAV

Berotralstat

Identification

Summary

Berotralstat is an inhibitor of plasma kallikrein used for prophylaxis of angioedema attacks in patients with hereditary angioedema.

Brand Names
Orladeyo
Generic Name
Berotralstat
DrugBank Accession Number
DB15982
Background

Berotralstat is a selective inhibitor of plasma kallikrein used in the prophylaxis of attacks of hereditary angioedema (HAE).5 It works by blocking the enzymatic activity of plasma kallikrein in releasing bradykinin, the major biologic peptide that promotes swelling and pain associated with attacks of HAE.3 Berotralstat is strictly used to prevent, but not treat, these attacks.4

Developed by BioCryst Pharmaceuticals, berotralstat is marketed under the name Orladeyo as oral capsules.1 Berotralstat was first approved by the FDA on December 3, 2020, as the first once-daily oral therapy to prevent angioedema attacks of HAE in adults and pediatric patients 12 years and older.5 Berotralstat was approved by the European Commission on April 30, 2021 7 and by Health Canada on June 06, 2022.6

Type
Small Molecule
Groups
Approved
Structure
3D
Similar Structures
Weight
Average: 562.573
Monoisotopic: 562.210422133
Chemical Formula
C30H26F4N6O
Synonyms
  • (+)-1-(3-(aminomethyl) phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride
  • (R)-1-(3-(aminomethyl) phenyl)-N-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride
  • 2-[3-(aminomethyl)phenyl]-N-[5-[(R)-(3-cyanophenyl)-(cyclopropylmethylamino)methyl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
  • BCX7353
  • Berotralstat
External IDs
  • BCX 7353
  • BCX-7353
  • BCX7353
  • WHO 10907
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Pharmacology

Indication

Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks.5,7,8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prophylaxis ofAcute attack of hereditary angioedema•••••••••••••••••• ••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials.1 Berotralstat inhibits plasma kallikrein in a concentration-dependent.5 In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks.4

In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner.5

Mechanism of action

Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway.1 It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein.2

Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK).5 During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE.3,5 Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks.5 Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation.2,5

TargetActionsOrganism
APlasma kallikrein
inhibitor
Humans
Absorption

The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 nghr/mL (range: 1880 to 3790 nghr/mL) and 1600 nghr/mL (range: 950 to 4170 nghr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours.5

Volume of distribution

The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat.5

Protein binding

Plasma protein binding is approximately 99%.5

Metabolism

Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity.5

Route of elimination

Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces.5

Half-life

Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours.5

Clearance

There is no information on the clearance rate.

Adverse Effects
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Toxicity

There is no information on the LD50 or overdose of berotralstat.

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
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interactions in your software
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Berotralstat.
AbemaciclibThe serum concentration of Berotralstat can be increased when it is combined with Abemaciclib.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Berotralstat.
AbrocitinibThe serum concentration of Berotralstat can be increased when it is combined with Abrocitinib.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Berotralstat.
Food Interactions
  • Take with food. This is instructed by the prescribing information of berotralstat. A high-fat meal had no significant effects on the Cmax and AUC of berotralstat, but the Tmax was delayed by 3 hours.

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Product Ingredients
IngredientUNIICASInChI Key
Berotralstat hydrochloride88SH1NBL2B1809010-52-3XFZLBLTUANGZBD-QDSLRZTOSA-N
International/Other Brands
Orladeyo (BioCryst)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OrladeyoCapsule150 mgOralBiocryst Pharmaceuticals Inc2022-09-06Not applicableCanada flag
OrladeyoCapsule150 mgOralBio Cryst Ireland Limited2022-06-06Not applicableEU flag
OrladeyoCapsule110 mg/1OralBioCryst Pharmaceuticals Inc.2020-12-04Not applicableUS flag
OrladeyoCapsule150 mgOralBio Cryst Ireland Limited2022-06-06Not applicableEU flag
OrladeyoCapsule150 mg/1OralBioCryst Pharmaceuticals Inc.2020-12-04Not applicableUS flag

Categories

ATC Codes
B06AC06 — Berotralstat
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
XZA0KB1BDQ
CAS number
1809010-50-1
InChI Key
UXNXMBYCBRBRFD-MUUNZHRXSA-N
InChI
InChI=1S/C30H26F4N6O/c31-24-10-9-22(28(37-17-18-7-8-18)21-5-1-3-19(11-21)15-35)13-25(24)38-29(41)26-14-27(30(32,33)34)39-40(26)23-6-2-4-20(12-23)16-36/h1-6,9-14,18,28,37H,7-8,16-17,36H2,(H,38,41)/t28-/m1/s1
IUPAC Name
1-[3-(aminomethyl)phenyl]-N-{5-[(R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl]-2-fluorophenyl}-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
SMILES
NCC1=CC(=CC=C1)N1N=C(C=C1C(=O)NC1=CC(=CC=C1F)[C@H](NCC1CC1)C1=CC=CC(=C1)C#N)C(F)(F)F

References

General References
  1. Hwang JR, Hwang G, Johri A, Craig T: Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema. Immunotherapy. 2019 Dec;11(17):1439-1444. doi: 10.2217/imt-2019-0128. Epub 2019 Oct 22. [Article]
  2. Aygoren-Pursun E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M: Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema. N Engl J Med. 2018 Jul 26;379(4):352-362. doi: 10.1056/NEJMoa1716995. [Article]
  3. Schmaier AH: Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease. Front Med (Lausanne). 2018 Jan 25;5:3. doi: 10.3389/fmed.2018.00003. eCollection 2018. [Article]
  4. Drugs.com: FDA Approves Orladeyo [Link]
  5. FDA Approved Drug Products: ORLADEYO (berotralstat) capsules, for oral use [Link]
  6. GlobeNewswire News Release: BioCryst Announces Health Canada has Authorized ORLADEYO® (berotralstat), the Only Oral Treatment for the Prevention of Hereditary Angioedema Attacks [Link]
  7. EMA Approved Drug Products: Orladeyo (berotralstat) oral capsules [Link]
  8. Health Canada Approved Drug Products: ORLADEYO (Berotralstat) oral capsules [Link]
Human Metabolome Database
HMDB0304862
ChemSpider
81368516
RxNav
2467540
PDBe Ligand
0RI
Wikipedia
Berotralstat
PDB Entries
7n7x

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingPreventionHereditary Angioedema (HAE)1
3Active Not RecruitingTreatmentHereditary Angioedema (HAE) / Pediatric1
3CompletedPreventionHereditary Angioedema (HAE)2
2CompletedPreventionHereditary Angioedema (HAE)1
2CompletedTreatmentHereditary Angioedema (HAE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral110 mg/1
CapsuleOral150 mg
CapsuleOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10125102No2018-11-132035-03-09US flag
US10689346No2020-06-232035-03-09US flag
US10662160No2020-05-262039-11-01US flag
US10329260No2019-06-252035-03-09US flag
US11117867No2021-09-142039-11-01US flag
US11230530No2015-03-092035-03-09US flag
US11618733No2019-11-012039-11-01US flag
US11708333No2015-03-092035-03-09US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00238 mg/mLALOGPS
logP4.8ALOGPS
logP5.58Chemaxon
logS-5.4ALOGPS
pKa (Strongest Acidic)13.35Chemaxon
pKa (Strongest Basic)9.29Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area108.76 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity149.32 m3·mol-1Chemaxon
Polarizability55.92 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
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/MSsplash10-03di-1000090000-377d08ad15e75e9004df
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03dl-0001090000-488710551bb20c269aac
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-074i-9020180000-a12ce0df28c07c1e6029
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gw0-2154950000-7f0b780e3a6c557c9ba9
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-0313790000-517c3d10cb585234c40c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-03mi-5530940000-57a1abf05a9c89212546
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Plasma kallikrein
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen an...
Gene Name
KLKB1
Uniprot ID
P03952
Uniprot Name
Plasma kallikrein
Molecular Weight
71369.205 Da
References
  1. Hwang JR, Hwang G, Johri A, Craig T: Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema. Immunotherapy. 2019 Dec;11(17):1439-1444. doi: 10.2217/imt-2019-0128. Epub 2019 Oct 22. [Article]
  2. Aygoren-Pursun E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M: Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema. N Engl J Med. 2018 Jul 26;379(4):352-362. doi: 10.1056/NEJMoa1716995. [Article]
  3. FDA Approved Drug Products: ORLADEYO (berotralstat) capsules, for oral use [Link]

Enzymes

Details1. Cytochrome P450 2D6
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
According to the prescribing information of berotralstat, berotralstat at a dose of 150 mg is a moderate inhibitor of CYP2D6.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: ORLADEYO (berotralstat) capsules, for oral use [Link]
Details2. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
According to the prescribing information of berotralstat, berotralstat at a dose of 150 mg is a moderate inhibitor of CYP3A4.
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: ORLADEYO (berotralstat) capsules, for oral use [Link]

Transporters

Details1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
According to the prescribing information of berotralstat, berotralstat at a dose of 300 mg is a P-gp inhibitor.
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: ORLADEYO (berotralstat) capsules, for oral use [Link]
Details2. ATP-binding cassette sub-family G member 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: ORLADEYO (berotralstat) capsules, for oral use [Link]

Drug created at December 08, 2020 18:56 / Updated at March 25, 2023 04:38