Nirogacestat

Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.

Exposure-Response Relationships

There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.

Cardiac Electrophysiology

At the recommended dosage, a mean increase in the QTc interval >20 ms was not observed.

Nirogacestat pharmacokinetic parameters in patients with desmoid tumors are summarized in Table 3.

Table 3. Pharmacokinetic Parameters and Characteristics of Nirogacestat:

^* Protein binding values reflect results from separate assays.

Abbreviations: AUC_0-tau = area under the time concentration curve to the dosing interval;
C_max = maximum plasma concentration; T_max = time to reach C_max; GMR = geometric mean ratio

Specific Populations

No clinically significant differences in the pharmacokinetics of nirogacestat were observed based on age (18 to 80 years), sex, race (Asian, Black or African American, and White), or mild or moderate renal impairment (eGFR ≥41 mL/min/1.73m²).

Effects of Hepatic Impairment

The mean AUC increased by up to 16% and the mean C_max decreased by up to 39% in subjects with moderate hepatic impairment identified by Child-Pugh Class B or NCI-ODWG Group C criteria compared to that of subjects with normal hepatic function.

Insufficient data are available to characterize nirogacestat PK in patients with severe hepatic impairment.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A inhibitors: Nirogacestat C_max increased by 2.5-fold and AUC by 8.2-fold following coadministration of a single dose of nirogacestat (100 mg) with itraconazole (a strong CYP3A inhibitor). Nirogacestat AUC is predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively.

Moderate CYP3A inhibitors: Nirogacestat AUC is predicted to increase by 2.73- and 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.

Strong CYP3A inducers: Nirogacestat AUC is predicted to decrease by 85% following coadministration of multiple doses of nirogacestat (150 mg BID) with rifampin (strong CYP3A inducer).

Moderate CYP3A inducers: Nirogacestat AUC is predicted to decrease by 67% following coadministration of multiple doses of nirogacestat (150 mg BID) with efavirenz (moderate CYP3A inducer).

CYP3A substrates: Midazolam (CYP3A substrate) C_max is predicted to increase by 1.77-fold and AUC by 2.07-fold following concomitant use with multiple doses of nirogacestat (150 mg BID).

CYP2C19 substrates: Concomitant use of multiple doses of nirogacestat (150 mg BID) with a drug that is a sensitive substrate of CYP2C19 decreases the plasma concentrations of these substrates.

P-gp substrates: Exposure to dabigatran (P-gp substrate) C_max and AUC were not affected by concomitant use with nirogacestat.

Drugs that increase gastric pH: Concomitant administration of proton pump inhibitors (e.g., omeprazole), histamine type 2 (H2)-receptor antagonists (e.g., famotidine), or antacids (e.g., calcium) is expected to reduce concentrations of nirogacestat.

Other Drugs

No clinically significant differences in nirogacestat pharmacokinetics were predicted when used concomitantly with cimetidine (weak CYP3A inhibitor).

No clinically significant differences were predicted in the pharmacokinetics of the following drugs when used concomitantly with nirogacestat: rosiglitazone (CYP2C8 substrate) or S-warfarin (CYP2C9 substrate).

In Vitro Studies

Nirogacestat does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

Nirogacestat is an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19, but does not induce CYP 1A2.

Transporter systems: Nirogacestat is a P-gp substrate, but not a substrate of BCRP, OATP1B1, and OATP1B3.

Nirogacestat is a P-gp inhibitor, but not an inhibitor of BCRP, MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT2 and OAT3.