Closed PriKalra closed 4 years ago
Is this explained by the effective concentration formula in PKSim where the Solubility/MW is a part of the equation? Or I am looking into something wrong here?
You are looking at the right place. Solubility limitation - in the (default) case No supersaturation
- is given by min(Solubility/MW ; M/Liquid)
. And Effective concentration in lumen
is what is used in all absorption processes.
For example for ketoconazole, I have the solubility at ref pH as 0.089 mg/l and I changed this parameter to 50 mg/l , in that case, the fraction dissolved is the same for both scenarios: 1
I guess your formulation is NOT Particle Dissolution
?
For Particle Dissolution
the transformations Solid <=> Dissolved [<=> Precipitated]
are modeled and fraction dissolved shown is what you would expect.
For all other oral formulation types: only one way transformation Solid => Dissolved
is modeled (according to your formulation). The back transformation Solid <= Dissolved
(which takes place as soon as solubility goes below intestinal concentration) is not modeled. Instead, effective intestinal concentration is cut at the solubility level (as you can see in the formula above). This is less physiological then in case of Particle Dissolution
but still an acceptable approximation.
Now when it comes to the fraction dissolved: what is shown is the total amount of dissolved drug according to the formulation. Thus de facto you will see here exactly the dissolution function of your oral formulation. E.g. if the formulation was Dissolved
you will see FDissolved = const = 1
disregarding your intestinal solubility. Which is.. well - probably not what your expect. What is important to know here: Fraction dissolved is just a derived output (observer) of a model. It is not used for any calculations.
Hi Yuri.
Thank you very much for the clarification. The dose formulation in my case was oral gavage and therefore I modeled it as dissolved
in PKSim. I am still confused a bit: as you stated that in the case of dissolved
formulation, it is disregarding intestinal solubility, does this implies that there is only the influence of solubility on the model? and therefore the models behavior is solubility restricted and not permeability restricted? And this is what we see in the Ketoconazole graph that I have attached in the first question?
This leads me to another question: now I wonder, it is clearly known that there is an interplay between solubility and permeability of drug absorption process'. How does one tackle the choice of permeability or solubility restricted models in PKSim?
I am still confused a bit: as you stated that in the case of dissolved formulation, it is disregarding intestinal solubility,
That was not the statement. In case of dissolved formulation (same as for any other oral formulation) intestinal solubility is taken into account in the absorption processes within Effective concentration in lumen
via min(Solubility/MW ; M/Liquid)
.
Just to be clear: models are ALWAYS solubility limited (unless you activate supersaturation - which is NOT the default case and makes sense only in combination with particles dissolution
)
Oh Sorry! Thank you! I understand now. :)
Dear All,
I am having difficulty in understand the basics of the impact of solubility of the compound (Solubility at ref. pH) on the absorption in PKSim. Previously I have worked with solubility restricted and non solubility restricted models. However, the following is not clear to me: 1) The influence of solubility on the absorption? 2) Where to exactly locate this equation in PKSim? 3) How do I have a non solubility restricted model in PKSim?
For example for ketoconazole, I have the solubility at ref pH as 0.089 mg/l and I changed this parameter to 50 mg/l , in that case, the fraction dissolved is the same for both scenarios: 1 However, the simulations show higher concentration in the venous blood with higher solubility. See below:
Is this explained by the effective concentration formula in PKSim where the Solubility/MW is a part of the equation? Or I am looking into something wrong here?
Thank you.
Best, Pri