Chemical formula: C₂₉H₃₅ClFN₇O₃ Molecular mass: 583.247 g/mol PubChem compound: 139377809
Sunvozertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR) that binds to and inhibits EGFR exon 20 insertion mutations at similar concentrations as wild-type EGFR.
In cultured cell models, sunvozertinib inhibited EGFR phosphorylation in cells expressing different EGFR exon 20 insertion mutation variants at approximately 2- to 10-fold lower concentrations than wild-type EGFR signaling inhibition. Sunvozertinib exhibited anti-tumor activity against xenograft models of NSCLC with EGFR exon 20 insertion mutations.
No clinically significant exposure-response relationships for overall response rate (ORR) were observed over the exposure range between sunvozertinib 200 mg and 300 mg (1.5 times the approved recommended dose).
At 1.5 times the approved recommended dose, a clinically significant QTc interval prolongation was not observed.
Sunvozertinib pharmacokinetics were observed at steady state at the approved recommended dosage and are presented as geometric mean (CV%) unless otherwise specified.
Sunvozertinib total systemic exposure (AUC) and maximum concentration (Cmax) increase approximately dose-proportionally across the dose range of 50 mg (0.25 times the approved recommended dose) to 400 mg (2 times the approved recommended dose). Steady state is reached within 15 days and the mean accumulation of AUC was approximately 3-fold. The steady-state Cmax and AUC of sunvozertinib were 412 (45%) ng/mL and 8,060 (42%) h*ng/mL, respectively.
Sunvozertinib median (minimum, maximum) time to maximum plasma concentration (tmax) is approximately 6 hours (3, 10 hours).
No clinically significant differences in sunvozertinib AUC and Cmax were observed following administration of sunvozertinib with a high-fat meal (approximately 1,000 calories, approximately 50% fat).
The apparent (oral) volume of distribution is 2,116 L (81%). Sunvozertinib plasma protein binding ranges from approximately 89% to 94% in vitro.
Sunvozertinib elimination half-life is 50 hours (27%) with an apparent (oral) clearance of 29 L/h (54%).
Sunvozertinib is primarily metabolized by CYP3A and forms the active demethylated metabolite, DZ0753. DZ0753 AUC represents 10% of the parent AUC.
Following a single oral dose of radiolabeled sunvozertinib, 79% of the dose was recovered in feces (7.3% unchanged) and 10% in urine (5.6% unchanged).
No clinically significant differences in the pharmacokinetics of sunvozertinib were observed based on age (19 to 96 years), sex, race (Asian 62%, White 28%, Black or African American 8%), body weight (30 to 118 kg), smoking status, mild to moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), and mild (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 x ULN and any AST) to moderate (bilirubin ≥1.5 to 3 x ULN and any AST) hepatic impairment. The effect of severe hepatic impairment (total bilirubin >3 x ULN and any AST) and severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of sunvozertinib has not been studied.
Strong CYP3A Inhibitors: Sunvozertinib AUC increased by 1.5-fold and Cmax by 1.3-fold following concomitant administration of itraconazole (strong CYP3A inhibitor) 200 mg once daily.
Strong and Moderate CYP3A Inducers: Sunvozertinib AUC decreased by 48% and Cmax by 38% following concomitant administration of carbamazepine (strong CYP3A inducer) 300 mg twice daily.
Sunvozertinib AUC is predicted to decrease by 44% following concomitant administration of efavirenz (moderate CYP3A inducer) 600 mg once daily.
CYP3A Substrates: Midazolam (sensitive CYP3A substrate) AUC decreased by 23% and Cmax by 15% following concomitant administration of sunvozertinib.
P-glycoprotein (P-gp) Substrates: Digoxin (P-gp substrate) AUC increased by 1.4-fold and Cmax by 1.2-fold following concomitant administration of sunvozertinib.
BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased by 1.4-fold and Cmax by 1.6-fold following concomitant administration of sunvozertinib.
Other Drugs:
No clinically significant effect on sunvozertinib pharmacokinetics is predicted following concomitant administration of fluconazole (moderate CYP3A inhibitor) 200 mg once daily.
No clinically significant effect on sunvozertinib pharmacokinetics is predicted following concomitant administration of dexamethasone (weak CYP3A inducer) 8 mg once daily.
No clinically significant effect on the pharmacokinetics of desipramine (CYP2D6 substrate) is predicted when used concomitantly with sunvozertinib.
No clinically significant effect on sunvozertinib pharmacokinetics was observed when used concomitantly with acid reducing agents (e.g. proton pump inhibitor).
CYP450 Enzymes: Sunvozertinib induces CYP2C8.
Transporter Systems: Sunvozertinib is a substrate of P-gp. Sunvozertinib inhibits OATP1B1.
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