Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib

Abstract

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib C_max but did lead to a 26% increase in sotorasib AUC_inf. CYP3A4 induction decreased sotorasib C_max by 35% and AUC_inf by 51%. OATP1B1/3 inhibition decreased sotorasib C_max and AUC_inf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.