Clinical Pharmacologist BMS, New Jersey, United States
Background: LXH254 is an adenosine triphosphate (ATP)-competitive inhibitor of the v-raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) and v-raf-1 Murine Leukemia Viral Oncogene Homolog 1 (CRAF) protein kinases and is currently under clinical development for the treatment of various cancers with mutations potentially amenable to LXH254. In this regard, various formulations of LXH254 (FMI, CSF1, CSF2) were developed for clinical development. A relative bioavailability study of LXH254 was performed under fasted state to compare the PK exposures (Cmax and AUC) of LXH254 from these formulations. Methods: This phase 1, randomized, open-label, three-period, six sequence crossover study was conducted in healthy volunteers. Participants received single doses of FMI, CSF1, and CSF2 in each period, with a 12-day washout period between doses. Plasma samples were collected intensively for 7 days post-dose. Geometric mean ratios (GMRs) of Cmax and AUC were generated to provide a comparison of exposure between the three different formulations. Results: The geometric mean ratios and the corresponding 90% CI of AUCinf and Cmax of the FMI formulation compared to the CSF1 formulation was 0.896 (90% CI: 0.836, 0.961) and 0.796 (90% CI: 0.701, 0.905), respectively. The geometric mean ratios and the corresponding 90% CI of AUCinf and Cmax of the FMI formulation compared to the CSF2 formulation was 0.914 (90% CI: 0.853, 0.980) and 0.882 (90% CI: 0.777, 1.0), respectively. The PK exposure of the FMI formulation was comparable with both CSF1 and CSF2 indicating comparable bioavailability across the formulations. The pharmacokinetic profiles of all three formulations were consistent, with no significant differences observed. No serious adverse events were reported during the study. Conclusion: The relative bioavailability of FMI was comparable to both CSF1 and CSF2, with all formulations exhibiting similar pharmacokinetic parameters. These findings support the interchangeability of FMI, CSF1, and CSF2 in clinical settings, supporting the use of the FMI formulation in later studies and post approval.
