PII-196 - A PHASE 1 STUDY OF THE PHARMACOKINETICS OF ADAGRASIB IN SUBJECTS WITH MILD, MODERATE, OR SEVERE RENAL IMPAIRMENT COMPARED TO SUBJECTS WITH NORMAL RENAL 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 renal impairment compared to subjects with normal renal function.

Methods: 31 subjects (10 normal renal function, 8, 7, and 6 subjects with mild, moderate or severe renal impairment, respectively) were enrolled and received a single 600 mg dose of adagrasib. Estimated creatinine clearance (CLcr) using the Cockcroft-Gault equation was used to assess renal function. Serial plasma and urine PK samples were collected from predose through 144 hours postdose. Plasma protein binding for adagrasib was assessed using plasma samples at 6-hour 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 renal function, the GLSM ratios (90% CIs) for Cmax and AUC∞ were 0.48 (0.25 – 0.95) and 0.56 (0.29 – 1.10), respectively, for subjects with mild renal impairment, 1.30 (0.55 – 3.09) and 1.30 (0.55 – 3.06), respectively, for subjects with moderate renal impairment, 0.98 (0.40 -2.42) and 1.24 (0.51 – 3.04), respectively, for subjects with severe renal impairment. The mean elimination half-life (t1/2) for normal renal function subjects (21.0 hours) was similar to subjects with mild, moderate, and severe renal impairment (23.2, 26.8, and 21.4 hours, respectively). Renal excretion of adagrasib was negligible in all impaired renal function groups with only 0.51% to 1.29% of the administered dose excreted in urine as unchanged adagrasib compared to 1.37% for subjects with normal renal function. Adagrasib was highly bound to plasma proteins (approximately 99.1% to 99.6% bound).

Conclusion: Renal impairment appeared to have no clinically meaningful effect on the single-dose PK of adagrasib. A single 600 mg oral dose of adagrasib was generally well-tolerated.