Re: Simulation settgin in the precence of Shrinkage in PK when doing PK-PD analysis
Hi Matts,
One method to investigate the problem would be to conduct VPC. If VPC with model-estimated variances provides good (not inflated) range of PK profiles then one can argue that the PK model provides good description of the data and can be used for simulations (including PK-PD).
Another test could be to do VPCs for the PK-PD model: one with fixed PK parameters (as was used in the sequential PK-PD modeling procedure) and the other one with model-simulated ETAs for both PK and PD parts. Again, if both provide good coverage of observed PK-PD data then combination of PK and PD models can be trusted, and any of the approaches can be applied. If one of the VPCs is inadequate, than it should be noticeable in the too narrow or too wide prediction intervals.
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Quoted reply history
On 2/18/2013 2:50 AM, "Kågedal, Matts" wrote:
> Hi nonmem users,
>
> I have a question related to shrinkage in PK when doing a sequential
> PK-PD analysis.
>
> Consider a situation with substantial shrinkage in the estimated
> individual PK (e.g. CL).
>
> When simulating PD based on dose from the model, it seems to me that
> variability in PD will be over-predicted if the estimated variability in
> CL (omega) is used.
>
> Would it then be appropriate to apply shrinkage to the variability in CL
> prior to simulating the PD?
>
> Does this have any practical consequences, and is meaningful to consider?
>
> I have mostly seen examples of consequences of shrinkage in the context
> of covariate analyses. Are there any examples relating to PK-PD
> analyses. E.g simultaneous, versus sequential?
>
> Consider for example the situations below:
>
> I.e. analysis performed by:
>
> 1.Derive individual PK parameters.
>
> 2.Relate posthoc plasma conc to PD
>
> If doing the analysis based on dose, any variability in PK will show up
> as variability in the dose-PD relationship.
>
> When doing the analysis based on plasma concentration (E.g. AUC), the
> PK-variability is accounted for by the PK-model and will not influence
> the variability in exposure response.
>
> However in the presence of shrinkage in the PK parameters, the situation
> should be somewhere in-between these two scenarios and some of the
> variability in PK will still show up as variability in PD.
>
> Hence when simulating based on the estimated variability in CL the
> variability in pd should theoretically be exaggerated.
>
> Regards,
>
> Matts Kågedal
>
> Senior Pharmacometrician
>
> AstraZeneca
>
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