Hi
I have sparse data from n=69 individuals from 3 dose levels, and rich
data from 1 individual at 1 dose level, following the deployment of a
drug eluting device. In the 69 individuals I have a single plasma
sample, and a single tissue sample (both collected at the same time
point). The sample time points range from 0.25 to 120 days (post
deployment), 2 individuals contributing at each time point. In the 1
individual I have greater than 8 sample points in each biophase.
The rich data from the 1 individual suggests 2 compartment disposition
in both plasma and tissue (a 4 compartment model described the data
quite well in WinNonLin). Pooling the sparse data at each dose level,
suggests 2 compartment disposition in both blood and plasma. My
questions are:-
1) Would you take a population approach to this data? - can mean
population parameters and their variability be robustly estimated?
2) Would you expect the parameters of a 4 cmpt model (8 thetas and
at least 4 omegas) to be reliably estimated with this data?
Any thoughts much appreciated.
Thanks
Hussain Mulla
Department of Pharmacy
University Hospitals of Leicester NHS Trust
Glenfield Hospital
Leicester
England
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Best approach with limited data
I am not sure that you can answer this question in general, without seeing the data. It may depend on the ratio of inter- to intra- individual errors. I would try it. One option could be to fix the variances of residual errors at values obtained from the full-profile subject. Also, you will need to restrict the number of etas (omegas) to at most 2 (one per measurement: not a firm rule but usually an upper estimate of the number of identifiable parameters). You may look on the fit or just make an educated guess where to put those etas. NONMEM (or bootstrap if you prefer to use CPU intensive methods) will give you precision of the estimates.
Leonid
Mulla Hussain - Senior Pharmacist wrote:
> Hi
>
> I have sparse data from n=69 individuals from 3 dose levels, and rich data from 1 individual at 1 dose level, following the deployment of a drug eluting device. In the 69 individuals I have a single plasma sample, and a single tissue sample (both collected at the same time point). The sample time points range from 0.25 to 120 days (post deployment), 2 individuals contributing at each time point. In the 1 individual I have greater than 8 sample points in each biophase.
>
> The rich data from the 1 individual suggests 2 compartment disposition in both plasma and tissue (a 4 compartment model described the data quite well in WinNonLin). Pooling the sparse data at each dose level, suggests 2 compartment disposition in both blood and plasma. My questions are:-
>
> 1) Would you take a population approach to this data? – can mean population parameters and their variability be robustly estimated?
>
> 2) Would you expect the parameters of a 4 cmpt model (8 thetas and at least 4 omegas) to be reliably estimated with this data?
>
> Any thoughts much appreciated.
>
> Thanks
>
> Hussain Mulla
>
> Department of Pharmacy
>
> University Hospitals of Leicester NHS Trust
>
> Glenfield Hospital
>
> Leicester
>
> England
>
> This e-mail, including any attached files, may contain confidential and / or privileged information and is intended for the exclusive use of the addressee(s) printed above. If you are not the addressee(s), any unauthorised review, disclosure, reproduction, other dissemination or use of this e-mail, or taking of any action in reliance upon the information contained herein, is strictly prohibited. If this e-mail has been sent to you in error, please return to the sender. No guarantee can be given that the contents of this email are virus free - The University Hospitals of Leicester NHS Trust cannot be held responsible for any failure by the recipient(s) to test for viruses before opening any attachments. The information contained in this e-mail may be the subject of public disclosure under the Freedom of Information Act 2000 - unless legally exempt from disclosure, the confidentiality of this e-mail and your reply cannot be guaranteed. Copyright in this email and any attachments created by us remains vested in the University Hospitals of Leicester NHS Trust.
I would use a population approach but would not pool the sparse data. I
think it would be appropriate to start with a 2 compartment model and
get the objective function. You can then try more compartment and see if
it improves the obj statistically. I have doubts about being able to fit
the 4 compartment model under that sampling design.
I would also perform a bootstrapping approach to assess quantitatively
the precision of all the model parameters.
Serge Guzy
_____
Quoted reply history
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Mulla Hussain - Senior Pharmacist
Sent: Wednesday, February 28, 2007 8:57 AM
To: [email protected]
Subject: [NMusers] Best approach with limited data
Hi
I have sparse data from n=69 individuals from 3 dose levels, and rich
data from 1 individual at 1 dose level, following the deployment of a
drug eluting device. In the 69 individuals I have a single plasma
sample, and a single tissue sample (both collected at the same time
point). The sample time points range from 0.25 to 120 days (post
deployment), 2 individuals contributing at each time point. In the 1
individual I have greater than 8 sample points in each biophase.
The rich data from the 1 individual suggests 2 compartment disposition
in both plasma and tissue (a 4 compartment model described the data
quite well in WinNonLin). Pooling the sparse data at each dose level,
suggests 2 compartment disposition in both blood and plasma. My
questions are:-
1) Would you take a population approach to this data? - can mean
population parameters and their variability be robustly estimated?
2) Would you expect the parameters of a 4 cmpt model (8 thetas and
at least 4 omegas) to be reliably estimated with this data?
Any thoughts much appreciated.
Thanks
Hussain Mulla
Department of Pharmacy
University Hospitals of Leicester NHS Trust
Glenfield Hospital
Leicester
England
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/ or privileged information and is intended for the exclusive use of the
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Hi,
The number of parameters, both the structural PK model and the
statistical model, would depend on the number of subjects and data
points as well as when they were collected in relation to the actual
time-course of the drug in both plasma and tissue. If your sampling time
provides enough information on a 2-comp model for each specimen, I don't
see why there would be any problems estimating the parameters. I am
uncertain if you can estimate any reliable parameters for your error
model since you only have 1 sample per subject.
What you might want to do is to make a graph of all your data and check
if you can "see" a bi-exponential conc.-time curve in both specimen.
Alternatively, make a graph of the mean values at each time-point and
check for the shape of the curve. Then start with the simplest model in
your plasma samples and continue to build it up with tissue data. For
the simple model, I would suggest using 1 ETA on the most plausible
parameter (CL or VC). You can always test addition of more ETAs once you
have your structural PK model in place.
Toufigh
Quoted reply history
________________________________
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Mulla Hussain - Senior Pharmacist
Sent: Wednesday, February 28, 2007 8:57 AM
To: [email protected]
Subject: [NMusers] Best approach with limited data
Hi
I have sparse data from n=69 individuals from 3 dose levels, and rich
data from 1 individual at 1 dose level, following the deployment of a
drug eluting device. In the 69 individuals I have a single plasma
sample, and a single tissue sample (both collected at the same time
point). The sample time points range from 0.25 to 120 days (post
deployment), 2 individuals contributing at each time point. In the 1
individual I have greater than 8 sample points in each biophase.
The rich data from the 1 individual suggests 2 compartment disposition
in both plasma and tissue (a 4 compartment model described the data
quite well in WinNonLin). Pooling the sparse data at each dose level,
suggests 2 compartment disposition in both blood and plasma. My
questions are:-
1) Would you take a population approach to this data? - can mean
population parameters and their variability be robustly estimated?
2) Would you expect the parameters of a 4 cmpt model (8 thetas and
at least 4 omegas) to be reliably estimated with this data?
Any thoughts much appreciated.
Thanks
Hussain Mulla
Department of Pharmacy
University Hospitals of Leicester NHS Trust
Glenfield Hospital
Leicester
England
This e-mail, including any attached files, may contain confidential and
/ or privileged information and is intended for the exclusive use of the
addressee(s) printed above. If you are not the addressee(s), any
unauthorised review, disclosure, reproduction, other dissemination or
use of this e-mail, or taking of any action in reliance upon the
information contained herein, is strictly prohibited. If this e-mail has
been sent to you in error, please return to the sender. No guarantee can
be given that the contents of this email are virus free - The University
Hospitals of Leicester NHS Trust cannot be held responsible for any
failure by the recipient(s) to test for viruses before opening any
attachments. The information contained in this e-mail may be the subject
of public disclosure under the Freedom of Information Act 2000 - unless
legally exempt from disclosure, the confidentiality of this e-mail and
your reply cannot be guaranteed. Copyright in this email and any
attachments created by us remains vested in the University Hospitals of
Leicester NHS Trust.