Fatal France clinical trial and the lessons learned: Application of in silico approaches to investigate the disposition of B1A10-2474 and possible safety concerns
Purpose: Recent France clinical trial with the drug coded, B1A10-2474, turned out to be a safety failure due to the death of a participant and several adverse events involving other participants who were on multiple dosing. An attempt was made in this study to investigate if any possible caution could have been detected by early predictions by in silico methods.
Methods: The physiochemical properties of B1A10-2474 were obtained using ADMETTM predictors which were further inputted into SimCYPTM simulator to investigate the drug disposition in healthy subjects.
Results: B1A10-2474 had linear pharmacokinetics, tendency to accumulate, follow multiple compartment dispositions with a delayed phase of elimination, and high brain permeability with a linear relation with blood plasma concentrations.
Conclusion: Due to high brain permeability and possible accumulation in brain with multiple dosing, B1A10-2474 is a high alert drug. In silico approaches utilized in this study generated a safety caution for B1A10-2474 and hence these tools can be used in early drug development processes.
Keywords: B1A10-2474, French trial, SimCYP, PBPK, ADMET, Phoenix NLME
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