EP-006 - AN OPEN-LABEL STUDY TO ASSESS THE EFFECT OF COADMINISTRATION OF SOTORASIB ON THE PHARMACOKINETICS OF ROSUVASTATIN, A BREAST CANCER RESISTANCE PROTEIN SUBSTRATE, IN HEALTHY SUBJECTS.

P. Cardona, S. Hutton, J. Purkis, T. Varrieur, B. Houk, S. Dutta; Amgen Inc., Thousand Oaks, CA, USA.

Background: Sotorasib is a small molecule KRASG12C inhibitor approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. In vitro studies indicate that sotorasib is a breast cancer resistance protein (BCRP) inhibitor. This study evaluated the effect of coadministration of sotorasib on the pharmacokinetics (PK) of rosuvastatin, a BCRP substrate, in healthy subjects.

Methods: This Phase 1, open-label, fixed-sequence cross-over study enrolled 13 healthy subjects. Each subject received 10 mg rosuvastatin on Day 1 (reference) and 960 mg sotorasib with 10 mg rosuvastatin on Day 6 (test) orally under fasted conditions. Blood samples were collected predose and up to 120 hours post dose. Plasma concentrations were measured using a validated method. PK parameters were estimated using non-compartmental methods. Safety was monitored throughout the study.

Results: After coadministration of 960 mg sotorasib with 10 mg rosuvastatin, rosuvastatin median time to maximum plasma concentration (Cmax) was similar compared to that when rosuvastatin was administered alone. Geometric mean Cmax and AUCinf (area under the curve from time zero to infinity) were 3.80 ng/mL and 36.2 h*ng/mL, respectively when administered alone, compared to 6.47 ng/mL and 48.4 h*ng/mL, respectively when coadministered with sotorasib. The geometric least squares means ratios (test/reference) for Cmax and AUCinf were 1.70 and 1.34, respectively.
There were no new safety signals for sotorasib.

Conclusion: This study concludes that sotorasib is a weak BCRP inhibitor. Rosuvastatin AUCinf and Cmax increased by approximately 34% and 70%, respectively when coadministered with sotorasib. These results suggest only BCRP substrates with a narrow therapeutic index would require monitoring when coadministered with sotorasib.