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Intravenous infusion with two compartments

i.v. infusion two compartments individual PK distributional kinetics

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#1 amitte

amitte

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Posted 12 January 2023 - 10:17 AM

Dear Certara Team

 

I am conducting a PK analysis on a rich/dense dataset from an study with an continuous i.v. infusion over 90 minutes (no bolus).

Previous NCA analysis seem to indicate distributional kinetics. The kinetics seem to be similar to for instance propofol; elimination is rapid and distribution into deeper compartments is slow. The concentration rises rapidly within the first 20 - 30 minutes, then slowly until reaching steady state at about 70 -80 minutes. After stopping the infusion, the concentration decreases rapidly initially (propably reflecting elimination from plasma/interstitium) and then more slowly (reflecting redistribution from tissue).

 

I am now setting up an individual PK model with your least squares regression models. I use a two compartment model (micro-constants, model 9). However, even though the fitted models look more or less ok on diagnostic plots (obs. vs. pred. and residual plots, weighted correlation 0.93), the fitted parameters don't really make sense. k12 is much smaller than k21 and V1 is much larger than V2, even though I would expect the exact opposite (small V1 reflecting plasma/interstitium, large V2 reflecting deeper tissues). Also, the variances of many parameter estimates are extremly inflated, indicating that something is clearly wrong.

 

Any suggestions what is wrong? Is it the wrong model for these rather unusual kinetics, where elimination is faster than distribution? Do I need to use user supplied bounds?

 

Many thanks in advance for your help

 

Sev

 

 

 



#2 bwendt@certara.com

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Posted 12 January 2023 - 01:07 PM

Hi Sev,

 

you might have been trapped in a local minimum. You can avoid that by starting with a simpler model. And I would not use the least squares regression model, rather I would suggest using the Phoenix model. When you setup your 1-compartment IV-Infusion model you can go to the Initial Estimates tab on the bottom panel where you can manually move the sliders to adjust initial values for V and ke.  would suggest you take volume estimates from your NCA analysis. Once you are satisfied, just execute the model, review the results. When the results are acceptable you can copy and paste the Phoenix model object back to the workflow. Make sure you accept fixed effects under the Parameters>>Fixed Effects tab. Now you can extend your model by adding a peripheral compartment, you can use the drop down in the Structure Tab to do that. Next step is going back to the Initial estimates tab and adjusting values for k12, k21, etc.I Please have a go and let us know if you run into issues.

 

Bernd

 



#3 amitte

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Posted 12 January 2023 - 01:57 PM

Dear Bernd

 

Thank you for your quick reply and advice. I will have a try with your iterative approach. What do you mean exactly by "Phoenix Models"? Are these the models under Modeling --> Maximum Likelihood Models?

 

Sev



#4 bwendt@certara.com

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Posted 12 January 2023 - 02:27 PM

Exactly. If you find it too difficult, let me know, we can schedule a remote session where I can show you how to deal with it.

 

Bernd






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