12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.

12.2 Pharmacodynamics

Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.

Cardiac Electrophysiology

At the recommended dose of 150 mg once daily, ORLADEYO does not prolong the QT interval to any clinically relevant extent. At 3 times the recommended dose, the mean (upper 90% confidence interval) increase in QTcF was 15.9 msec (23.5 msec). The observed increase in QTcF was concentration-dependent.

12.3 Pharmacokinetics

Following oral administration of berotralstat 150 mg once daily, the steady-state Cmax and area under the curve over the dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL), respectively. Following oral administration of berotralstat 110 mg once daily, the steady-state Cmax and AUCtau are 97.8 ng/mL (range: 63 to 235 ng/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL), respectively.

Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days 6 to 12. After once-daily administration, exposure of berotralstat at steady state is approximately 5 times that after a single dose.

The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.

Absorption

The median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours).

Effect of Food

No differences in the Cmax and AUC of berotralstat were observed following administration with a high-fat meal, however the median Tmax was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed).

Distribution

Plasma protein binding is approximately 99%. After a single dose of radiolabeled berotralstat 300 mg, the blood to plasma ratio was approximately 0.92.

Elimination

The median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours).

Metabolism

Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro. After a single oral radiolabeled berotralstat 300 mg dose, berotralstat represented 34% of the total plasma radioactivity, with 8 metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity.

Excretion

After a single oral radiolabeled berotralstat 300 mg dose, approximately 9% was excreted in urine (3.4% unchanged; range: 1.8 to 4.7%) and 79% was excreted in feces.

Specific Populations

Body weight, age, gender, and race did not have a clinically meaningful influence on the systemic exposure of berotralstat.

Geriatric Patients

Based on the population pharmacokinetic analyses that included elderly patients (≥65 to 74 years, N=25), age does not have a clinically meaningful impact on the systemic exposure of berotralstat [see Use in Specific Populations (8.5)].

Pediatric Patients

Based on population pharmacokinetic analyses that included pediatric patients 12 to <18 years of age, exposure at steady state following oral administration of berotralstat 150 mg once daily was approximately 20% higher compared to adults. The higher exposure in adolescents is not considered to be clinically meaningful.

Patients with Renal Impairment

The pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min). When compared to a concurrent cohort with normal renal function (CLCR greater than 90 mL/min), no clinically relevant differences were observed; Cmax was increased by 47%, while AUC0-last was increased by 14% [see Use in Specific Populations (8.6)].

The pharmacokinetics of berotralstat has not been studied in patients with End-Stage Renal Disease (CLCR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).

Patients with Hepatic Impairment

The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in subjects with mild, moderate, and severe hepatic function (Child-Pugh Class A, B, and C, respectively). The pharmacokinetics of berotralstat were unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment, Cmax was increased by 77%, while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increased by 27%, while AUC0-last was decreased by 5%. The median half-life of berotralstat was increased by 37% and 22% in patients with moderate and severe hepatic impairment, respectively, in comparison to healthy subjects. The percent of unbound berotralstat increased 2-fold from a mean of 1.2% in healthy subjects to a mean of 2.4% in subjects with severe hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Effect of Other Drugs on the Pharmacokinetics of ORLADEYO

Berotralstat is a P-gp and BCRP substrate. Cyclosporine, a P-gp and BCRP inhibitor, decreased berotralstat 150 mg Cmax by 7%, while AUC0-last and AUC0-inf increased by 27% and 24%, respectively.

Effect of ORLADEYO on the Pharmacokinetics of Other Drugs

Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19.

Berotralstat at a 300 mg dose is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).

Co-administration of berotralstat 150 mg once daily with 0.15 mg/0.03 mg desogestrel/ethinyl estradiol led to a 2.6-fold increase in the AUC0-last of etonogestrel, the active metabolite of desogestrel.

The effect of berotralstat on the pharmacokinetics of other drugs are presented in Figure 1 [see Drug Interactions (7.2)].

Figure 1: Effect of ORLADEYO on Concomitant Medications