Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein (PKa). By inhibiting PKa, sebetralstat blocks the cleavage of high molecular weight kininogen (HK) and the subsequent generation of bradykinin (BK), thereby halting HAE attack progression which is associated with increased vascular permeability and oedema formation. Sebetralstat also suppresses the activation of positive feedback mechanism of the kallikrein-kinin system (KKS), thereby reducing factor XIIa (FXIIa) and additional PKa production.
After a dose of 300 mg, sebetralstat was rapidly absorbed with peak plasma concentrations occurring at approximately 1 hour.
In an evaluation of food effect, no difference in the AUC of sebetralstat was observed following a dose of 600 mg with a high-fat meal. There was an approximately 29% reduction in Cmax, and median Tmax was delayed by 2 hours. Sebetralstat was administered without regard to food in clinical safety and efficacy trials, and can be taken with or without food.
Plasma protein binding in humans is approximately 77%. After a dose of 600 mg radiolabelled sebetralstat, the blood to plasma ratio of radioactivity was approximately 0.65. The geometric mean apparent volume of distribution (Vz/F) was 208 L after a dose of 300 mg.
After a dose of 300 mg, the geometric mean elimination half-life of sebetralstat was 3.7 hours. The geometric mean apparent clearance (CL/F) was 38.5 L/h.
Sebetralstat is primarily metabolised by CYP3A4 in vitro. Sebetralstat is an in vitro substrate of P-glycoprotein and BCRP. After a dose of 600 mg radiolabelled sebetralstat, sebetralstat represented 64.1% of the total plasma radioactivity AUC0-24, with 11 metabolites, each accounting for between 0.39% and 7.1% of the total radioactivity AUC0-24. The most prevalent plasma metabolite is not pharmacologically active.
Sebetralstat is an in vitro inhibitor of CYPs 3A4 and 2C9, and of the transporters OAT3, OCT2, MATE1, MATE2-K, OATP1B1 and OATP1B3.
Sebetralstat is an in vitro inducer of CYP3A4. Given its intermittent use and its rapid absorption and elimination, the risk of CYP3A4 induction is considered not to be clinically significant.
After a dose of 600 mg radiolabelled sebetralstat to healthy male subjects, approximately 32% of radioactivity was excreted in urine and 63% was excreted in faeces. Approximately 8.7% and 12.5% of the dose was recovered in the urine and faeces, respectively, as unchanged sebetralstat. Sebetralstat is mainly eliminated by hepatic metabolism via the faeces.
Across a dose range of 5 mg to 600 mg, the Cmax of sebetralstat was proportional to dose; the AUC was greater than dose proportional, likely due to emergence of a longer terminal elimination phase at higher doses.
The pharmacokinetics of 600 mg sebetralstat were studied in patients with mild and moderate hepatic impairment (Child-Pugh Class A or B). In patients with mild hepatic impairment Cmax was increased by 7% and AUC by 16% compared to patients with normal hepatic function. In patients with moderate hepatic impairment, Cmax was increased by 63% and AUC was increased by 100%. In patients with moderate hepatic impairment who are taking a strong CYP3A4 inhibitor a single dose of 300 mg is recommended when treating an HAE attack.
Sebetralstat is not primarily renally eliminated and is not administered as a chronic treatment. Sebetralstat pharmacokinetics have not been studied in patients with renal impairment.
KONFIDENT did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was demonstrated to be rapid, with near complete (≥95%) suppression of plasma kallikrein as early as 15 minutes after dosing with 300 mg sebetralstat in patients with HAE.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Carcinogenicity of sebetralstat was evaluated in a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats. There were no increases in malignant tumours and no evidence of carcinogenicity in either species at any dose level. Exposure at the highest doses (on an unbound plasma AUC basis) were 0.2 and 0.4 times the maximum recommended human dose (MRHD) in male and female mice respectively, and 5.7 times MRHD in rats.
In a fertility study conducted in rats, there was no effect on mating or fertility at any dose level while an increase in preimplantation loss was observed at the high dose level of 600 mg/kg/day (7.7 times human exposure at the MRHD based on unbound AUC levels). Embryofetal development studies were conducted in rats and rabbits. In rats, sebetralstat and/or its metabolites was shown to cross the placenta; malformations (cleft palate, ventricular septal defect) and embryofetal lethality were reported at 600 mg/kg/day (12 times human exposure at the MRHD based on unbound AUC levels); the no observed adverse effect level for embryofetal development was 300 mg/kg/day (3.0-times human exposure at the MRHD based on unbound AUC levels). In rabbits, no malformations or embryo-fetal lethality were observed at doses up to 300 mg/kg/day (6.8-times human exposure at the MRHD based on unbound AUC levels); potential developmental effects associated with PKa inhibition may not have been fully captured in rabbits due to interspecies difference in pharmacological activity of sebetralstat. There were no adverse developmental effects in a rat pre- and-post natal development study at doses up to 450 mg/kg/day.
Administration of a single dose of radiolabelled sebetralstat to lactating rats resulted in similar concentrations of total radioactivity in milk and plasma, with the maximum concentration observed at 1 hour post dose. By 24 hours post dose mean levels of radioactivity in both milk and plasma were close to background.
Environmental risk assessment studies have shown that sebetralstat has the potential to accumulate and may persist in some aquatic sediment systems.
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