Hi,
I don't understand Leonid's reluctance to use methods that deal with BLQ
measurements. In this case I would certainly use a NONMEM code which
uses BLQ information appropriately e.g. with Beal's M3 method.
I don't think the code is complicated (see pdf link below for examples)
and there are clear theoretical advantages which seem to be supported by
a number of simulation studies (more complicated code examples in Ahn et
al).
In addition to the issue of a change of assay you should also look out
for a change in formulation which might mean there is delayed absorption
accounting for a lag time - it may not simply be a question of a higher
LLOQ.
Nick
http://holford.fmhs.auckland.ac.nz/docs/censored-observations-with-nonmem.pdf
1. Xu XS, Dunne A, Kimko H, Nandy P, Vermeulen A. Impact of low
percentage of data below the quantification limit on parameter estimates
of pharmacokinetic models. J Pharmacokinet Pharmacodyn. 2011;38(4):423-32.
2. Bergstrand M, Karlsson MO. Handling data below the limit of
quantification in mixed effect models. AAPS J. 2009;11(2):371-80.
3. Byon W, Fletcher CV, Brundage RC. Impact of censoring data below
an arbitrary quantification limit on structural model misspecification.
J Pharmacokinet Pharmacodyn. 2008;35(1):101-16.
4. Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based
approaches to handling data below the quantification limit using NONMEM
VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401-21.
On 13/12/2011 7:10 a.m., Leonid Gibiansky wrote:
Toufigh
If you treat BQLs as missing (rather than zeros), BQL observations in
the older study should not interfere with the model. This would be
similar to the project with several studies with different sampling
schedules. Alternative is to treat BQLs using one of the more advanced
methods (you can have different LLOQs for different studies in this
case) but this involves using a more complicated code, Laplacian
option, etc.: I would not do it unless you tried all other options and
cannot get a good fit. If assays are different you may want to test
assay effect on residual variability.
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 12/12/2011 2:24 PM, Toufigh Gordi wrote:
Dear all,
I am involved in a project, where data from several different studies
are pooled and a PK model is being developed. The studies were conducted
over a period of time and the bioanalytical assay was improved during
this period. Hence, 2 of these studies have a LOQ of 1 ng/mL, while the
others have a LOQ of 20 ng/mL. This results in all samples, including
the very early ones, showing detectable levels of the compound for the 2
studies, while the others indicate an apparent lag-time, since the older
bioanalysis was not sensitive to detect the low concentrations at the
beginning of the dosing.
Any comments on how to deal with this situation?
Toufigh
Toufigh Gordi, PhD
President, PK/PD and Clinical Pharmacology Services
Rosa & Co. LLC: www.rosaandco.com <http://www.tgordi.com/>
E-mail: [email protected] <mailto:[email protected]>
Tel.: 408-480-7314
Fax: 408-370-9810
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