From: "Bonate, Peter" -
Subject: [NMusers] Time of day as a covariate
Date: 2/9/2004 3:53 PM

Hi, everyone.

I am working on a drug where the time of day the drug was
administered is important as a covariate for V1 (p = 0.003).
I have a few ideas for why this may be happening, but I'd like
to hear from anyone who might have their own opinion about
possible mechanisms.

More importantly is how to report this unusual finding.  For
instance, how might Vdss be reported in the product label. 
Would you even try to put this in the label?  Any thoughts on
how to present this data would be helpful.  Actually, any thoughts
on this at all would be appreciated.

This is a Pandora's box I wish I had never opened.

Thanks alot everyone,


Peter L. Bonate, PhD, FCP
Director, Pharmacokinetics
ILEX Oncology
4545 Horizon Hill Blvd
San Antonio, TX  78229
phone: 210-949-8662
fax: 210-949-8219

From: Nick Holford -
Subject: Re: [NMusers] Time of day as a covariate
Date: 2/9/2004 8:47 PM


What do you mean by 'important'? IMHO a P value has no
merit by itself to justify a labelling claim. 

What is the magnitude of the effect on V1 in relation to
time? Is the clinical benefit or adverse effects related to
concentrations e.g. peak conc, that might be strongly influenced
by variation in V1? Is there a clinically relevant reduction in
the between subject variability of V1 when you account for time
of day? What is the route of adminstration and what kind of subjects?
Healthies? Patients? What kind of disease?

Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand tel:+64(9)373-7599x86730 fax:373-7556

From: "Bonate, Peter" -
Subject: Re: [NMusers] Time of day as a covariate
Date: 2/10/2004 2:15 AM

Dear Peter,

There are many possible reasons, to be considered after Nick's comments 
bout clinical significance of course.
I would consider:

- Protein binding, since tissue partition, Kp, is a function of Kp for 
he unbound drug (Kpu) and fu. Kpu is often assumed to be invariant even
across species (it depends upon what the particular drug binds to in
the tissue though).

- Blood cell distribution, which would affect fu

- Since I note your are in an oncology company, perhaps
comedications which could affect tissue distribution through
the above mentioned mechanisms, plus perhaps interaction with
tissue transporters.

- Components of food could affect many of these mechanisms.

- If the drug is not delivered parenterally, is the V1 you are
considering really V/F, therefore the variation could be due to F?

Best regards, Phil.

Philip Lowe PhD
Head of Modelling and Systems Biology
Clinical Development & Medical Affairs
Novartis Pharmaceuticals AG
CH-4002 Basel

Subject: Re: [NMusers] Time of day as a covariate
Date: 2/10/2004 2:24 AM


Just to add to Nick's comments below, would this "statistically significant"
difference merit a change in dose depending on the time of day the drug is
administered? If not, does it need to or should it even enter the label?


From: Joel S. Owen -
Subject:  Re: [NMusers] Time of day as a covariate
Date: 2/11/2004 7:17 PM

 Hi Pete,

In addition to the traditional consideration of changes in plasma protein
binding, one might also consider fluctuation in binding to other bio-molecules
which might have diurnal variation.  Examples of time-of-day variation in
hormonal regulation and DNA synthesis are given in:

Borst DW, Mahoney WB. 
Diurnal changes in mouse mammary gland DNA systhesis. 
J Exp Zool. 1980 Nov;214(2):215-218.

Schell, H, Schwarz W, hornstein OP, Bernlochner W, Weghorn C.
Evidence of diurnal variation of human epidermal cell proliferation. 
I. Epidermal 3H-labeling index and serum cortisol rhythm. 
Arch Dermatol Res. 1981:271(1):41-47

We have used such a consideration as a modeling approach in which time-dependent
variation in Rmax was introduced into a model of target mediated pharmacokinetics
such as described (without dirunal variation) in
Mager DE, Jusko WJ. 
General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition.
J Pharmacokinet Pharmacodyn 2001. 28:507-532.

Best regards,


Joel S. Owen, Ph.D.
Director PK/PD
Cognigen Corporation
395 S. Youngs Road
Buffalo, NY 14221
(v) (716) 633-3463 ext. 247
(f) (716) 633-7404