Absorption, Distribution and Excretion
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 ng*hr/mL (range: 1880 to 3790 ng*hr/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/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.
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.
The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat.
There is no information on the clearance rate.

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Metabolism / Metabolites
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.

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Biological 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.

Hepatotoxicity
In preregistration trials, mild, transient serum aminotransferase elevations occurred in 2% to 5% of patients receiving berotralstat vs 10% of those on placebo. Values above 5 times the upper limit of normal (ULN) were uncommon (less than 1%). Furthermore, bilirubin levels remained normal and no patient developed symptomatic acute liver injury. In many instances, other causes for the liver test abnormalities were present including preexisting nonalcoholic fatty liver disease, chronic viral hepatitis, or gallstone disease. Nevertheless, occasional patients required drug discontinuation because of liver test abnormalities. Since its licensure and more widescale clinical use, there have been no published reports of acute liver injury attributed to berotralstat.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Berotralstat is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. No information is available on the excretion of berotralstat into breastmilk. Because berotralstat is about 99% bound to plasma proteins, the amounts in milk are likely to be very low. If berotralstat is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not 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 inhibitor of plasma kallikrein used in the prophylaxis of attacks of hereditary angioedema (HAE). 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. Berotralstat is strictly used to prevent, but not treat, these attacks. Developed by BioCryst Pharmaceuticals, berotralstat is marketed under the name Orladeyo as oral capsules. 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. Berotralstat was approved by the European Commission on April 30, 2021 and by Health Canada on June 06, 2022.
Berotralstat is a Plasma Kallikrein Inhibitor. The mechanism of action of berotralstat is as a Kallikrein Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor.
Berotralstat is a small molecule inhibitor of plasma kallikrein that is used to prevent acute attacks of hereditary angioedema (HAE) in adults and children 12 years of age or older. Berotralstat has been linked to occasional mild-to-moderate elevations in serum aminotransferase levels during therapy but has not been implicated in instances of clinically apparent liver injury with symptoms or jaundice.
See also: Berotralstat Hydrochloride (active moiety of).

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Drug 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.
Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older.
Treatment of hereditary angioedema

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Mechanism of Action
Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. 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. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). 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. 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. 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.

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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. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT 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.)