Simulation results

Phoenix Certara Forums Modelling and Simulation
1

Hi

I am simulating PD response from lower dose to higher dose using eta values, different occasion of simulation under same dose & condition i am getting different responses. Kindly let me know the possible reasons,

Procedure adopted while simulation;

  • Copied & accepted final estimates from final PD model
  • Dose units are same

Thanks

Sundar. M

2

Are you able to share your model or better yet project file so we can look at your other settings?

3

Hi,

Please find uploaded project file.

Now i am getting different kind of issue, i.e getting almost similar simulated profile even double the dose.

Thanks

Sundar. M

Forum-project.phxproj (1.29 MB)

4

Hi

Have you had a chance to review my project file.

I have checked all possible mapping and its correct as per my knowledge. However, i am not able to understand the results, why its same for different dose level simulation.

Thanks

Sundar. M

5

Hi,

In continuation to above post, while reviewing the individual subject’s simulated profile, simulated profile of 3 subjects observed with -1.#IND (for all time points) instead of numerical value for one of the replicate (total replicates n=100).

Is it because of any error?

Thanks

Sundar. M

6

Hi Sundar, sorry for the delay. I would be interested to see your original fits since the random error (omegas) are very large.

to Demonstrate, try this in R

1.69304 * exp(rnorm(100, 0, sqrt(2.5395776)))

This is structural parameter gam simulation.

You will see that some gamma values are very large (more than 100) when normally beween 0.5 and 8 might be expected.

Using that values as a power leads to overflow.

I’d suggest to reduce ngam

Simon

7

Hi Simon,

Thanks for your information, due to confidentiality reasons, i am not able to share the original fits project file.

I will try to reduce ngam and post the outcome.

Thanks
Sundar. M

8

Sundar, it’s more a case of being sure that your original fit is good and you have confidence in all the model parameters before you start uisng them for simulation.

9

Simon, I agree your point, however still i have following uncertainty,

—even with worst model - doubling the dose will not differentiate the simulation results?

—simulated results are comparable with observed results (for eg., 30mg observed vs simulated) - how to buy then the validity of developed model?

Thanks

Sundar. M

10

Without seeing your data, bur certainly in biological systems a saturation effect can be expected and the model should include that e.g. heart rate cannot increase beyond perhaps 200BPM for even a young healthy adult.

if you model matches well at observed doses that’s great but again with PKPD models it’s good to assess a minimum of three dose levels to better understand the dose response curve, is it sigmoid, or simple emax or a more complicated indirect response? etc.

you may also want to consider if there is a placebo effect you need to first build as your baseline model if your PD varies over time e..g cortisol levels within a day, tumour growth, other disease progression.

this course maybe interesting to you, it’s available in person and online;

https://www.certarauniversity.com/learn/course/external/view/classroom/29/200-CLIntermediatePKPDModelingusingPhoenixWinNonlin