Absorption, Distribution and Excretion
Following the first dose, berottripstat reaches steady-state plasma concentrations within 6 to 12 days. With once-daily dosing, the peak steady-state plasma concentration (Cmax) and area under the curve (AUC) of berottripstat are approximately five times that of a single dose. After once-daily oral administration of berottripstat, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the 150 mg dose group and 97.8 ng/mL (range: 63 to 235 ng/mL) at the 110 mg dose group. The area under the curve (AUCτ) over the dosing interval was 2770 nghr/mL (range: 1880 to 3790 nghr/mL) and 1600 nghr/mL (range: 950 to 4170 nghr/mL) at the 110 mg dose. The median time to peak concentration (Tmax) in the fasting state is 2 hours, which is delayed to 5 hours after a high-fat meal. Tmax ranges from 1 to 8 hours. Following a single oral dose of 300 mg of radiolabeled berottripstat, approximately 9% of the drug is excreted in the urine, of which 1.8% to 4.7% of the radiolabeled compound is unmetabolized parent drug. Approximately 79% of the drug is excreted in the feces. Following a single dose of 300 mg of radiolabeled berottripstat, the plasma concentration-to-dose ratio is approximately 0.92. Clearance information is currently unavailable. Metabolites/Metabolites: Berottripstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathways and metabolites of berottripstat are not well understood. Following a single oral dose of 300 mg of radiolabeled berottripstat, approximately 34% of the total plasma radioactivity is the parent drug, and approximately eight detectable metabolites account for 1.8% to 7.8% of the total radioactivity.

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Biological Half-Life
Following a single oral dose of 300 mg of radiolabeled berottripstat, the median elimination half-life of berottripstat is approximately 93 hours, ranging from 39 to 152 hours.

Hepatotoxicity
In pre-registration trials, 2% to 5% of patients treated with berottripnical experienced mild, transient elevations in serum transaminases, compared to 10% in the placebo group. Transaminases exceeding the upper limit of normal (ULN) by 5 times were uncommon (less than 1%). Furthermore, bilirubin levels remained normal, and no patients developed symptomatic acute liver injury. In many cases, liver dysfunction is caused by other factors, including pre-existing non-alcoholic fatty liver disease, chronic viral hepatitis, or gallstones. Nevertheless, a small number of patients require discontinuation of the drug due to liver dysfunction. Since its approval and widespread clinical use, there have been no published reports of acute liver injury caused by berottripnical. Probability Score: E (Unproven, but suspected as a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Bellotrastulstat is a plasma kallikrein inhibitor indicated for the prevention of hereditary angioedema. There is currently no information on whether berottractul is excreted into breast milk. Because berottractul binds to plasma proteins at a rate of approximately 99%, its concentration in breast milk is likely to be very low. If a mother needs to take berottractul, she should not discontinue breastfeeding. Until more data is available, especially during the nursing of newborns or premature infants, alternative medications may be preferred.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Plasma protein binding is approximately 99%.

: Sohtome Y, Sodeoka M. Development of Chaetocin and S-Adenosylmethionine Analogues as Tools for Studying Protein Methylation. Chem Rec. 2018 Dec;18(12):1660-1671.

Berotralstat is a selective kallikrein inhibitor used to prevent attacks of hereditary angioedema (HAE). Its mechanism of action involves blocking the enzymatic activity of kallikrein, inhibiting the release of bradykinin. Bradykinin is the main bioactive peptide that promotes swelling and pain associated with HAE attacks. Berotralstat is for the prevention of HAE attacks only and is not intended for treatment. Developed by BioCryst Pharmaceuticals and marketed under the brand name Orladeyo, berotralstat is available in oral capsule form. On December 3, 2020, berotralstat received its first approval from the U.S. Food and Drug Administration (FDA), becoming the first once-daily oral HAE prevention medication for adults and children aged 12 years and older. On April 30, 2021, berotralstat received approval from the European Commission; and on June 6, 2022, it received approval from Health Canada. Berotralstat is a kallikrein inhibitor. Bellotrostat's mechanism of action is as a kallikrein inhibitor, cytochrome P450 2D6 inhibitor, cytochrome P450 3A4 inhibitor, and P-glycoprotein inhibitor. Bellotrostat is a small-molecule plasma kallikrein inhibitor used to prevent acute exacerbations of hereditary angioedema (HAE) in adults and children aged 12 years and older. Mild to moderate elevations in serum transaminase levels occasionally occur during treatment with bellotrostat, but have not been found to be associated with clinically significant liver damage (with symptoms or jaundice). See also: Bellotrostat hydrochloride (active ingredient). Drug Indications Bellotrostat is indicated for the prevention of acute exacerbations of hereditary angioedema (HAE) in adults and children aged 12 years and older. It is not used to treat acute exacerbations of hereditary angioedema (HAE). Orladeyo is indicated for the routine prevention of relapses of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older.
Treatment of Hereditary Angioedema

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Mechanism of Action
Hereditary angioedema (HAE) is a rare genetic disorder characterized by severe swelling of the skin and upper respiratory tract. It is caused by mutations in the regulatory or coding regions of the gene encoding a C1 inhibitor (SERPING1), resulting in a deficiency (Type I) or dysfunction (Type II) of the C1 inhibitor (C1 esterase inhibitor, C1-INH). The C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high molecular weight kininogen (HMWK) to generate cleaved high molecular weight kininogen (cHMWK). During an episode of hereditary angioedema (HAE), plasma kallikrein levels decrease, leading to the cleavage of high molecular weight kininogen and the release of bradykinin. Bradykinin is a potent vasodilator that increases vascular permeability. Bradykinin plays a crucial role in promoting edema and pain associated with hereditary angioedema (HAE). Due to a deficiency or dysfunction of serum C1 inhibitors, HAE patients are unable to properly regulate plasma kallikrein activity, leading to an uncontrolled increase in plasma kallikrein activity and triggering recurrent episodes of angioedema. Berottroxate is a potent plasma kallikrein inhibitor whose mechanism of action is to control excessive bradykinin production by binding to plasma kallikrein and blocking its proteolytic activity.

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Pharmacodynamics
Berotroxate prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excessive bradykinin production in patients with hereditary angioedema (HAE). Clinical trials have shown that berottroxate has a rapid onset, long duration of action, and good tolerability. Berottroxate inhibits plasma kallikrein in a concentration-dependent manner. Clinical trials have shown that berottroxate reduces the incidence of HAE attacks at 24 weeks, and the effect can last up to 48 weeks. Clinical trials have also found that once-daily doses of berottrastatin exceeding 150 mg can lead to QT interval prolongation in a concentration-dependent manner.

C30H26F4N6O

562.560659885406

562.21

1809010-50-1

Berotralstat dihydrochloride;1809010-52-3

137528262

White to off-white solid powder

4.5

3

9

9

41

938

1

FC1C=CC(=CC=1NC(C1=CC(C(F)(F)F)=NN1C1C=CC=C(CN)C=1)=O)[C@@H](C1C=CC=C(C#N)C=1)NCC1CC1

UXNXMBYCBRBRFD-MUUNZHRXSA-N

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

1-[3-(aminomethyl)phenyl]-N-(5-{(R)-(3- cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

ORLADEYO BCX-7353 BCX 7353BCX7353

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~177.76 mM)

Solubility in Formulation 1: ≥ 8.5 mg/mL (15.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 85.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)