DMDG Open 2024 -- Non-specific binding of drugs to microsomes can profoundly influence the outcome of in vitro metabolism assays and represents a key consideration in the calculation of kinetic parameters associated with drug-drug interaction (DDI) investigations or in vitro-in vivo extrapolations based on scaling of intrinsic clearance data. Recent regulatory guidance documents advocate the determination of the microsomal free fraction (fumic) and recommend that protein concentrations “are usually less than 1 mg/mL” (FDA, 2020) or “should be minimised” (ICH, 2024). Labcorp cytochrome P450 inhibition investigations include the determination of the fumic parameter in our standard study design. In this retrospective review, we have collated data from 39 recent studies to identify the proportion of compounds which show significant binding at typical incubation concentrations and the protein and concentration dependency of this binding. These data can provide a better understanding of assay conditions where binding has a high impact and facilitates the potential streamlining of processes with regard to experimental complexity and timelines.

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