RE: Random effect on ALAG between dose events
Hi Tingjie,
I agree with Leonid's first remark. The natural way to account for the random
effect associated with each dosing occasion is to use the dosing occasion as
the covariate and implement the covariate effect using between occasion
variability. You only need to have enough occasions to cover the number of
doses which have an observation in the subsequent interval for the subject who
had the most such occasions. I have used BOV for twice daily dosing over
several months but only needed 40 occasions to describe all the patients in a
large study.
You should also be thinking of BOV on bioavailability as well as lag time.
Also consider testing whether BSV for these absorption parameters is greater
than zero once you have included BOV. From a mechanistic viewpoint dose to dose
variation in absorption may be primarily due to between occasion rather than
between subject differences.
Best wishes,
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72
email: [email protected]
http://holford.fmhs.auckland.ac.nz/
http://orcid.org/0000-0002-4031-2514
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Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Leonid Gibiansky
Sent: Wednesday, 12 August 2020 2:35 PM
To: Tingjie Guo <[email protected]>; NMusers <[email protected]>
Subject: Re: [NMusers] Random effect on ALAG between dose events
No, there is no other solution except IOV.
One option to lessen the impart of the discrepancy is to have inflated residual
error in the some interval post-dose
;TAD: time after dose
SD=THETA()
IF(TAD.LE.XX) SD=SD*THETA()
$ERROR
Y=TY*(1+SD*EPS(1))
$SIGMA
1 FIX
Then observations close to the dose (with uncertain dose time) will have less
influence on PK parameters.
Regards,
Leonid
On 8/12/2020 4:51 AM, Tingjie Guo wrote:
> Dear NMusers,
>
> I'm modeling a PK data set with a discrepancy between the documented
> dosing time and the actual dosing time. According to our clinical
> practice, actual dosing time is always >= documented time. I added a
> ALAG with IIV to address this issue using the following formulation.
>
> ALAG1 = THETA(5) * EXP(ETA(5))
>
> This indeed improved the model fitting quite a lot. However, this
> parameterization does not reflect the reality as I expect the ETAs
> should vary between each dosing event rather than only between patients.
> So I expect a "inter dose event variability" would better make sense to
> this end. Since there are too many dosing events per patients, a
> IOV-like approach is doable but not preferred. And it may not accurately
> reflect "inter dose event variability" either. I was wondering if there
> is any good solution to this problem? Any comments are very much
> appreciated!
>
> Warm regards,
> Tingjie Guo
>