Identification

Name
Berotralstat
Accession Number
DB15982
Description

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 Developed by BioCryst Pharmaceuticals, berotralstat is taken once-daily as oral capsules.1 Under the market name Orladeyo, berotralstat was approved by the FDA on December 3, 2020, as the first oral, once-daily therapy to prevent angioedema attacks of HAE in adults and pediatric patients 12 years and older. In clinical trials, berotralstat was shown to significantly reduce attack rates at 24 weeks compared to placebo, which was sustained through 48 weeks. Berotralstat is strictly used to prevent, but not treat, these attacks.4 Previous oral therapies used for prophylaxis of HAE attacks, such as androgens, were limited by undesirable adverse effects and several contraindications.2 In clinical trials, berotralstat displayed a fast onset of action, long duration of action, and acceptable tolerance in patients.1

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 562.573
Monoisotopic: 562.210422133
Chemical Formula
C30H26F4N6O
Synonyms
  • Berotralstat
External IDs
  • BCX 7353
  • BCX-7353
  • BCX7353
  • WHO 10907

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

Associated Conditions
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. It has a fast onset of action, long duration of action, and acceptable tolerance.1 Berotralstat inhibits plasma kallikrein in a concentration-dependent. 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.

Affected organisms
Not Available
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
AbemaciclibThe serum concentration of Berotralstat can be increased when it is combined with Abemaciclib.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Berotralstat.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Berotralstat.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Berotralstat.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Berotralstat.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Berotralstat.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Berotralstat.
AfatinibThe serum concentration of Berotralstat can be increased when it is combined with Afatinib.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Berotralstat.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Berotralstat.
Additional Data Available
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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.

Products

Product Ingredients
IngredientUNIICASInChI Key
Berotralstat hydrochloride88SH1NBL2B1809010-52-3XFZLBLTUANGZBD-QDSLRZTOSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OrladeyoCapsule110 mg/1OralBioCryst Pharmaceuticals Inc.2020-12-04Not applicableUS flag
OrladeyoCapsule150 mg/1OralBioCryst Pharmaceuticals Inc.2020-12-04Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Classification
Not classified

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. [PubMed:31635497]
  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. [PubMed:30044938]
  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. [PubMed:29423395]
  4. Drugs.com: FDA Approves Orladeyo [Link]
  5. FDA Approved Drug Products: ORLADEYO (berotralstat) capsules, for oral use [Link]
ChemSpider
81368516

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingPreventionHAE / Hereditary Angioedema1
3Active Not RecruitingPreventionHereditary Angioedema, HAE1
2CompletedPreventionHereditary Angioedema (HAE)1
2CompletedTreatmentHereditary Angioedema (HAE)1
2, 3Active Not RecruitingPreventionHAE / Hereditary Angioedema / Prophylaxis1
1CompletedTreatmentHereditary Angioedema4
Not AvailableApproved for MarketingNot AvailableHAE / Hereditary Angioedema / Prophylaxis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral110 mg/1
CapsuleOral150 mg/1
Prices
Not Available
Patents
Not Available

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
Not Available

Targets

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. [PubMed:31635497]
  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. [PubMed:30044938]
  3. FDA Approved Drug Products: ORLADEYO (berotralstat) capsules, for oral use [Link]

Enzymes

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]
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

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]
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 on December 08, 2020 11:56 / Updated on December 11, 2020 14:53

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