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
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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