PII-040 - THE IMPACT OF MILD, MODERATE AND SEVERE LIVER DYSFUNCTION ON THE PHARMACOKINETIC DISPOSITION OF MEZIGDOMIDE

B. Kiesel¹, A. Shahane¹, J. Burnett¹, X. Wang¹, C. Sychterz¹, Z. Guo¹, F. Shakeel¹, Y. Zhu², A. Gaudy¹; ¹Bristol Myers Squibb, Princeton, NJ, USA, ²Bristol Myers Squibb, Princeton, NJ, 07901.

Background: Mezigdomide (MEZI) is a novel, potent oral cereblon-E3 ligase modulator (CELMoD™) demonstrating clinical activity for multiple myeloma (MM). PK of MEZI is dependent on CYP3A metabolism which may be limited by hepatic impairment (HI). To characterize MEZI PK and support treatment guidelines in MM patients with HI, a clinical trial was conducted in volunteers with varying degrees of HI. A PopPK model was also applied to evaluate PK data and HI in the MM population.

Methods: 32 subjects (8 per group) with mild, moderate, and severe HI and a healthy control group were enrolled per Child-Pugh (CP) criteria into study CA057-1010 (NCT05707390) and treated with a single 0.4 mg MEZI dose. Dose selection was guided by PBPK which predicted a modest increase in exposure due to HI. Plasma samples were collected and concentrations of MEZI, M3, and M4 were analyzed by LC-MS/MS. PK was assessed using noncompartmental analysis. Statistical analysis was conducted between the healthy control group and HI groups by generating geometric mean ratios (GMR) and 90% confidence intervals (CI) of exposure. HI, categorized by NCI ODWG criteria, was assessed as a covariate of PK in MM patients by a PopPK model and data from CC-92480-MM-001.

Results: Compared to the healthy control group MEZI AUC0-∞ trended upward with worsening HI although significance was limited to severe HI (1.65 GMR, 1.08 – 2.52 90% CI) per CP categorization. Results for AUC0-∞ were similar per NCI-ODWG categorization with significance limited to severe HI with GMR of 1.94 (1.07 - 3.54 90% CI), although sample size by this categorization was limited (N= 21 normal, 3 mild, 5 moderate, 2 severe). HI did not have an impact on M3, while M4 exposure increased with increasing HI. PopPK analysis using NCI-ODWG HI categorization in the MM population was limited to normal and mild HI (N= 129 normal, N = 26 mild HI) and did not identify HI as a significant covariate.

Conclusion: Mild or moderate HI did not impact MEZI PK. Severe HI resulted in an approximate 60% to 2-fold increase in MEZI exposure by CP and NCI ODWG categorization, respectively. These results suggest no dose modification is necessary for mild or moderate HI. Dose reduction for severe HI may be considered with clinical exposure-response results to ensure patient safety and appropriate benefit-risk.