Release Notes of Model Versions?

[StephanSchaller]

Should there be release Notes of Model Versions?

Here, a prominently placed Info IF (or not) this model Version (i.e. the used input parameters) differs in any extent to the published model would be very helpful.

Thoughts?

[Incei]

If any deviation occurs from the previous released version, this could be mentioned in the model repository "release" section for each model, not in the model library;
In case we want to automize this process after a new osp release at some point, it will then still need for each model a seperate note. With increasing amount of models, I think therefore its not that practical.

[StephanSchaller]

I didn't specify WHERE this should be noted ;-)
Release notes could also be part (appendix? Or separately created document?) of the evaluation report. If there are no changes beyond the OSP SUite Version, this should be rather easy to add?

[Incei]

@StephanSchaller Well..since you posted this question it in this repository... :)

I would add it to the release notes of the model repository, as mentioned before, not the report...with the reason as mentioned previously. Would that not suffice?
I think the document itself should be a clean one ready for any kind of usage. I dont see the additional value of adding release notes into the report, and on the title page there is already a link to the model repositories etc and their respective versions.

What do you think?

[StephanSchaller]

and on the title page there is already a link to the model repositories etc and their respective versions.

Not sure I can find the way to the versions. It is all a bit messy to navigate.
How do you get to the release after accessing the Model Library?...

There is only a linked vice versa... GitHub really is not the place to make these things accessible easily...

[Incei]

There is always place for improvement :), but honoustly i dont agree with you :)

To answer your question: e.g. in the library you open raltegravir , then e.g. click on the online version of the report: raltegravir_evaluation_report.md, there on the first page (on top) you find a link to the following as below

• Version --> 1.1-OSP9.0 ( which means model release version 1.1 created wit osp 9.0)
• based on Model Snapshot and Evaluation Plan --> "https://github.com/Open-Systems-Pharmacology/Raltegravir-Model/releases/tag/v1.1",

The link to the model snapshot opens the release repository for that model where you e.g. could then also find the release notes.

[StephanSchaller]

then e.g. click on the online version of the report:

And you think that is intuitive / easy to find? ;-)
But yes,

There is always place for improvement :)

[Incei]

I do :)

[StephanSchaller]

Then we have to agree to disagree ;-)

[prvmalik]

Hi guys. Does altering mucosal permeability work better to represent the midazolam-itraconazole DDI? Old model by Hanke et al. 2018 underestimated ratios at 6.5 approx, but observed were 7-10.

Answered my own question - yes it does! Much better.

[StephanSchaller]

@prvmalik, good idea. But can you elaborate how (what direction) and from which compound you have altered mucosal permeability. And how did it affect (improve) the model and all of the other DDIs?

[prvmalik]

Hi @StephanSchaller I was just asking about the work already done by (I think) @sfrechen on midazolam. He used the strategy of optimizing mucosal permeability to capture gut wall metabolism with CYP3A4 rt-pcr profile, since the rt-pcr profile under-estimates gut wall expression of 3a4. The model has been updated in the library.

[StephanSchaller]

since the rt-pcr profile under-estimates gut wall expression of 3a4

Is this a conclusion or is there actual (more up-to-date) data on gut wall 3a4 expression levels?

[prvmalik]

It's a modeling conclusion. Don't have too much time to write why but here's a brief:

In a scenario where:
Drug is metabolized exclusively by cyp3a4
Drug has a low-moderate hepatic extraction ratio (< 0.3 - 0.4)
Drug is not a substrate for intestinal efflux transporters
Drug does not have solubility limit to oral absorption
Drug has moderate-high cellular permeability (commonly driven by lipophilicity >2)

Modeling requirements:
Volume of distribution confirmed by IV PK profile
CYP3A4 metabolism evaluated with DDI scenario

Overall F = Fa x Fg x Fh
Recall Fh = (1 - hepatic ER)
If Fa is high >0.8
yet overall F < 0.4
you can conclude that you have Fg < 1 and significant gut wall metabolism.
RTPCR CYP3A4 expression does not provide sufficient CYP3A4 expression in gut to capture this Fg.

With the RTPCR CYP3A4 expression profile, capturing gut wall metabolism of midazolam required increasing residence time in the gut mucosa. Even with this adjustment the DDI with itraconazole cannot be reconciled because the increase in bioavailability (30-40% to 80-90% in the DDI scenario) is not characterized (see calculation method Les Benet 2020). Of course this may also be explained by a low estimate of fu in gut.