Berotralstat

Breast Feeding; Lactation; Milk, Human; Serine Proteinase Inhibitors

EMA approved medicines: Human medicine

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.

B - Blood and blood forming organs

QB - Blood and blood forming organs

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.

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.