PII-195 - A PHASE 1 STUDY OF THE PHARMACOKINETICS OF ADAGRASIB IN SUBJECTS WITH MILD, MODERATE, OR SEVERE HEPATIC IMPAIRMENT COMPARED TO SUBJECTS WITH NORMAL HEPATIC FUNCTION.

C. Cilliers¹, P. McCloskey¹, J. Morin², J. Tran¹; ¹Mirati Therapeutics, ²Innovaderm Research.

Background: This phase I study evaluated the pharmacokinetics of adagrasib in subjects with mild, moderate, or severe hepatic impairment compared to subjects with normal hepatic function.

Methods: 39 subjects (11 normal hepatic function, 8, 12, and 8 subjects with mild, moderate or severe hepatic impairment, respectively) were enrolled and received a single 600 mg dose of adagrasib. Child-Pugh (CP) classification was used to determine the level of hepatic impairment. Serial blood collections were obtained from predose through 144 hours postdose for analysis of plasma concentrations of adagrasib. Plasma protein binding for adagrasib was assessed using plasma samples at 4- and 24-hours postdose. Adagrasib PK parameters were derived with noncompartmental analysis. The geometric least square mean (GLSM) ratio and the 90% CI of the primary PK parameters (Cmax, AUClast, and AUC∞) were analyzed using an analysis of covariance (ANCOVA) model including group (3 test groups and the reference group), age, body weight, sex, and race.

Results: Compared to subjects with normal hepatic function, the GLSM ratios (90% CIs) for Cmax and AUC∞ were 0.94 (0.65 – 1.36) and 0.80 (0.51 – 1.26), respectively, for subjects with mild hepatic impairment, 0.70 (0.49 – 0.98) and 0.85 (0.55 – 1.30), respectively, for subjects with moderate hepatic impairment, 0.51 (0.35 – 0.73) and 1.03 (0.66 – 1.61), respectively, for subjects with severe hepatic impairment. The mean elimination half-life (t1/2) for matched control subjects (19.8 hours) was similar to subjects with mild hepatic impairment (20.7 hours), but longer in subjects with moderate and severe hepatic impairment (31.1 and 43.4 hours, respectively). Overall, the reduced absorption and slower elimination rate in subjects with moderate and severe hepatic impairment resulted in total exposure (AUC) relatively unchanged. Adagrasib fraction unbound (fu) was highly variable (CV% 38.9% to 116.2%) with no notable differences between subjects with normal hepatic function (0.96%) and subjects with hepatic impairment (1.22% to 1.69%).

Conclusion: No clinically meaningful differences in adagrasib total AUC were observed in subjects with mild to severe hepatic impairment (CP classes A to C) compared to subjects with normal hepatic function. A single 600 mg oral dose of adagrasib was generally well-tolerated.