Time of day as a covariate

From: "Bonate, Peter" - pbonate@ilexonc.com 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, pete 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 email: pbonate@ilexonc.com

From: Nick Holford - n.holford@auckland.ac.nz Subject: Re: [NMusers] Time of day as a covariate Date: 2/9/2004 8:47 PM Pete, 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 -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

From: "Bonate, Peter" - pbonate@ilexonc.com 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 Switzerland

From: michael.looby@pharma.novartis.com Subject: Re: [NMusers] Time of day as a covariate Date: 2/10/2004 2:24 AM Pete, 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? Mick

From: Joel S. Owen - joel.owen@cognigencorp.com 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 -- 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 (e) joel.owen@cognigencorp.com http://www.cognigencorp.com/ _______________________________________________________