Re: Different assays for different studies
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.
Quoted reply history
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
> >
> > *The information contained in this e-mail message, e-mail message
> > sequence, and/or any enclosures is confidential, and it may be
> > privileged and protected from unauthorized use and/or disclosure. If you
> > are not the intended recipient, any use, dissemination, distribution, or
> > copying is strictly prohibited. If you received this e-mail in error,
> > PLEASE NOTIFY THE SENDER immediately and destroy this message, any
> >
> > enclosures, and any copies of the message and/or the enclosures. Thank you.*
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: [email protected]
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford