Gedatolisib

Gedatolisib is a kinase inhibitor of class I PI3K isoforms (α, β, δ, γ) and mTOR complexes mTORC1 and mTORC2, resulting in downstream inhibition of multiple effectors, including AKT. In estrogen receptor (ER)-positive breast cancer cell lines and xenograft models harboring wild-type or mutant PIK3CA, gedatolisib induced apoptosis and anti-proliferative effects in vitro and reduced tumor cell growth in vivo. In a human ER-positive breast cancer xenograft model harboring a PIK3CA mutation, the combination of gedatolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or the doublet combinations.

Exposure-Response Relationships

The exposure-response relationship and time course of pharmacodynamic response for the effectiveness of gedatolisib have not been fully characterized. An increased incidence of stomatitis or mucositis (Grade 3 and 4), nausea, vomiting, hyperglycemia, and adverse reaction leading to dosage modification or discontinuation was observed with higher gedatolisib exposure at the dose range of 10 mg to 319 mg (0.06 to 1.8 times the approved recommended dose).

Cardiac Electrophysiology

At weekly doses up to 319 mg (1.8 times the recommended dose), clinically significant QTc interval prolongation was not observed.

Gedatolisib pharmacokinetic parameters were observed at the approved recommended dosage in patients with breast cancer and are presented as mean (% coefficient of variation [%CV]), unless otherwise specified. Gedatolisib maximum plasma concentration (C_max) is 13,700 (29%) ng/mL and area under the curve (AUC) is 21,400 (21%) ng·h/mL. Gedatolisib C_max and AUC values increase dose proportionally in the dose range 10 mg to 319 mg (0.06 to 1.8 times the recommended dose). No accumulation of gedatolisib is observed after once-weekly administration.

Distribution

Gedatolisib plasma protein binding is 98%, and is not concentration dependent, in vitro. Gedatolisib blood-to- plasma ratio is 0.87, in vitro. Gedatolisib volume of distribution is 393 L.

Elimination

Gedatolisib elimination half-life (t_1/2) is 36 hours with an estimated clearance of 8 (23%) L/hour.

Excretion

After a single dose of radiolabeled gedatolisib 89 mg to healthy subjects, approximately 67.4% of the dose was recovered in feces (67% unchanged) and 12.2% in urine (11.6% unchanged).

Specific Populations

No clinically significant effects on the pharmacokinetics of gedatolisib were observed based on age (21 to 84 years), sex, race (White [78%], Asian [9.1%], Black or African American [4.1%]) body weight (35 to 168 kg), mild hepatic impairment (total bilirubin ≤1.5 × ULN and any AST) or estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m² (MDRD equation). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, eGFR <45 mL/min/1.73 m², or dialysis on gedatolisib pharmacokinetics is unknown.

Drug Interactions

Clinical Studies and Model-Informed Approaches

No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with gedatolisib: metformin (MATE1, MATE2-K, and OCT1 substrate), rosuvastatin (BCRP substrate), or repaglinide (CYP2C8 sensitive substrate).

In vitro Studies

CYP450 Enzymes: Gedatolisib is not an inhibitor of CYP1A2, CYP2A6, or CYP2B6.

The ability of gedatolisib to induce CYP450 enzymes is unknown given the results of the vitro studies were inconclusive due to decreased viability of hepatocytes.

Transporter Systems: Gedatolisib is a substrate of P-gp and BCRP and is not a substrate for OATP1B1, OATP1B3, OCT1, NTCP, MRP2, or MRP3.

Gedatolisib did not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, and BSEP.