Interspecies scaling rat oral bioavailability and other problems

[OneWay289]

I am working with an OTC product that has no in vivo IV PK. Therefore, I am using interspecies scaling to convert from rat IV to rat oral and then to human oral. There is a good in vivo rat PK study (IV and oral) of the parent compound.

Metabolism of the parent compound is primarily by hydrolysis followed by multiple other phase 1 and or phase 2 routes. Approximately 1/3 of the metabolism is in the small intestines and up to 2/3 in the large intestines. Hydrolysis and some other phase 1 metabolisms are by bacterial enzymes. I am only tracking the disappearance of the parent compound with a PBPK model for now. F is 0.48% for the rat oral.

I have developed an IV rat PBPK model that is a fair fit for the in vivo PK results. Vss and MRT are a little high. T1/2 and Tmax are good fits. However, I have been unable to fit the rat oral. I assume that a large first-pass effect is responsible for the low bioavailability. Adding an unidentified metabolic enzyme in the Compound (expression in Individual) as given in OSP GitHub forum discussion #1433 resulted in an error “Using hepatic plasma clearance in conjunction with metabolism process might lead to more clearance than” (the error stopped there) in the Process portion of the Simulation. I ran the simulation anyway and got the following error when hovering over some of the PK-Analysis parameters: “Absorption seems to be incomplete, or absorption process is not finished.” The error then went on to say to compare Vd, Vss, MRT, etc. to the IV. These values were significantly different from the IV. The bioavailability was decreased but not enough and increasing the specific clearance for the unidentified metabolic enzyme did not result in a change in bioavailability. The curve fit was bad. Another warning noted that I should simulate as long as the GI process, but my observed data was only obtained for six hours, and I read that I am only supposed to simulate as long as the observed data was collected. I also added biliary clearance which was no help. Using the default specific intestinal permeability resulted in F=0 so I used an in-silico value of Peff.

Any help would be greatly appreciated!

Thanks!