P. H. Chan,1 M. AbuTarif,1 T. Eley,1 B. He,2 P. Yin,3 P. Sukumar,2 H. Kandoussi,1 J. Wang,1 R. Bertz1; 1Bristol-Myers Squibb, Lawrenceville, NJ, 2Bristol-Myers Squibb, Hopewell, NJ, 3Bristol-Myers Squibb, Wallingford, CT

BACKGROUND: BMS-986094 (INX-08189) is a HCV NS5B nucleotide prodrug that was discontinued due to potential cardiac toxicity in some patients; a marker of toxicity was reduced ejection fraction. In addition, abnormal S-T wave readings on EKG and elevations in brain naturetic peptide (BNP) were considered potential indicators for toxicity risk. Population pharmacokinetic (PPK) and exploratory exposure-safety analyses were performed after termination of the clinical program to examine possible relationships between systemic exposure of INX-08032 (major circulating metabolite of BMS-986094) and the aforementioned cardiac adverse event markers/indicators in a phase II study (AI472003) in subjects receiving BMS-986094 with peginterferon/ribavirin or daclatasvir.
METHODS: A PPK model for INX-08032 was developed using plasma concentrations from 112 HCV-infected subjects. Individual post-hoc INX-08032 daily AUC and cumulative AUC were plotted against BNP repeated longitudinal measurements and binary variables of EKG change and ejection fraction < 50%.
RESULTS: The final PPK model was a one-compartment linear model with first-order absorption and covariates of serum creatinine on volume and clearance, and baseline body weight on clearance. There was no apparent correlation between daily INX-08032 AUC and BNP measurements. Correlation between cumulative INX-08032 AUC and BNP is only apparent at higher cumulative AUC estimates. Subjects with abnormal S-T wave or ejection fraction < 50% appear to have higher cumulative INX-08032 exposure.
CONCLUSION: Higher cumulative exposures of INX-08032, but not steady state AUC, appear to be correlated with potential indicators of cardiac events associated with exposure to BMS-986094 in some patients.