From: "R.A.A. Mathot" r.mathot@erasmusmc.nl
Subject: [NMusers] modelling lag time and absorption
Date: Wed, 15 Nov 2006 17:07:34 +0100

Dear NM-users,

Currently I am working on the PK data of a drug that is taken once daily orally. I have data from 38
individuals with 8 samples per individual over an 8-hour period. Individual plots demonstrate that
a 1-compartment PK model adequately describes the data. Furthermore, the plots show that there is
considerable between-patient varibility in Ka, Tlag, V/F and CL/F. For instance, some patient had
detectable drug levels at the first sample taken wheras in 1 patient the 8 hour (=last) sample was
the first sample in which the drug could be detected. In the dataset concentrations <LOD were
excluded with the exception of the last sample before concentration > LOD or the first sample after
concentration > LOD. These concentrations were set at half the value of the LOD.

ADVAN2 was used with FOCE+interaction and a combined error model. The results were dissapoining:
1. biased PRED vs DV plots
2. High WRES values
3. Parameter estimates were dependent on the number of significant digits and intitial values
4. Individual plots of IPRED vs time demonstrated that Tlag was underestimated in 25% of the patients

I tried to improve the model by application of log-transformation (FOCE, additive error model, all
concentrations <LOD excluded). Diagnostic plots slightly improved (1 and 2 above) whereas parameter
estimates remained unstable and POSTHOC's of lag-time were underestimated (3 and 4).

What could be the possible reasons for these observations?
Thanks in advance for your time.

Ron Mathôt

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Ron A. A. Mathôt, PharmD PhD
Department of Clinical Pharmacy and Clinical Pharmacology
Erasmus MC
University Medical Center Rotterdam
P.O. Box 2040
3000 CA  Rotterdam
The Netherlands
Phone: +31 10 4633202
Fax  : +31 10 4636605
Email: r.mathot@erasmusmc.nl
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