Questions regarding PBPK modeling related to salt form

[NingJia012]

Hi everyone,

I have a question regarding the handling of salt forms in PK-Sim.

In my case, the compound was administered as the fumarate salt in all preclinical studies. The measured pKa and solubility were also determined using the fumarate salt, whereas the observed plasma concentrations were quantified as the free base.

My understanding is that after oral administration, the fumarate salt may dissolve and gradually precipitate as the free base in the gastrointestinal tract. This could prolong dissolution and absorption, which is consistent with our experimental observation that the fecal excretion fraction reaches its peak at around 72 hours.

However, in PK-Sim I have to define the compound as the free base. As a result, the model predicts that the compound is eliminated into feces much more rapidly than what is observed experimentally.

Has anyone encountered a similar situation?

How would you handle this in PK-Sim? Would you recommend adjusting specific parameters (e.g., dissolution, precipitation, intestinal permeability, or formulation-related parameters), or is there a better strategy to account for the delayed dissolution/precipitation behavior associated with administration as a salt?

Any suggestions or relevant experience would be greatly appreciated. Thanks!

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