- On 26 Feb 2003 at 17:04:46, Rostam Namdari (chista90.-at-.yahoo.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Colleagues,

Is it useful to conduct statistical tests

(e.g.,t-test, ANOVA) on PK parameters obtained on two

different cycles during the course of therapy? We may

conclude there is a statistical significance or not

but I am not sure what would be the use of these data

in terms of clinical/biological significance.

Rostam - On 27 Feb 2003 at 14:14:51, Nick Holford (n.holford.at.auckland.ac.nz) sent the message

Back to the Top

The following message was posted to: PharmPK

Rostam

Rostam Namdari wrote:

>

> Dear Colleagues,

>

> Is it useful to conduct statistical tests

> (e.g.,t-test, ANOVA) on PK parameters obtained on two

> different cycles during the course of therapy?

If you mean that the only difference between the two cycles is the

passage of time then most likely you can probably expect to find no

difference between the mean PK parameters on the two occasions. I

therefore agree that a t-test/ANOVA to test a null hypothesis that is

of dubious interest is unlikely to be useful.

However, there is strong interest in identifying and quantifying the

within subject variability in PK (and other) parameters. This has

practical benefits for improved modelling of PK parameters based on

mixed effect models (Karlsson & Sheiner) and also provides quantiative

criteria for deciding what process to use to individualize dose

(Holford 1999, 2001).

Karlsson MO, Sheiner LB. The importance of modeling interoccasion

variability in population pharmacokinetic analyses. Journal of

Pharmacokinetics & Biopharmaceutics 1993; 21(6):735-50.

Holford NHG. Target Concentration Intervention: Beyond Y2K. British

Journal of Clinical Pharmacology 1999;48:9-13.

Holford NHG. Concentration controlled therapy. In: Breckenridge A,

editor. Esteve Foundation Workshop. Amsterdam: Elsevier Science; 2001.

p. 135-144.

Nick Holford, Divn Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 27 Feb 2003 at 11:27:00, Rostam Namdari (chista90.at.yahoo.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Nick,

Thanks for your response. Is it true that generally

more than 20% increase in AUC from one treatment cycle

to another considered to be clinically significant?

How do we evaluate the clinical/biological

significance of drug accumulation based on PK data?

Any input from the group is appreciated.

Rostam - On 28 Feb 2003 at 09:36:39, Nick Holford (n.holford.aaa.auckland.ac.nz) sent the message

Back to the Top

The following message was posted to: PharmPK

Rostam,

Rostam Namdari wrote:

>

> Dear Nick,

> Thanks for your response. Is it true that generally

> more than 20% increase in AUC from one treatment cycle

> to another considered to be clinically significant?

There is no true answer to this question. Clinical significance is a

matter of judgment. As I tried to say before the issue is not the MEAN

change e.g. 20% but the VARIABILITY from cycle to cycle that is of

probably of more importance. The MEAN change is likely to be a random

variability so focussing on the differences between any two cycles is

not important.

However, if you happen to have real data with a consistent change from

the first to the second (or subsequent) cycle then you should be

thinking about time dependent changes in PK parameters e.g. like

carbamazepine which induces its own clearance.

> How do we evaluate the clinical/biological

> significance of drug accumulation based on PK data?

What EXACTLY (give me an equation) do YOU mean by drug accumulation?

Nick

Nick Holford, Divn Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 28 Feb 2003 at 13:24:51, Rostam Namdari (chista90.-a-.yahoo.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Nick and Jogarao,

Thanks for your comments and recommended reference.

Nick, regarding what I meant by drug accumulation, I

was referring to use of AUC (simply comaring the AUC

of the two cycles) or actual acummulation factor R =

AUCss/AUC0-t (t= dosing intervals).

Rostam - On 1 Mar 2003 at 10:52:58, Nick Holford (n.holford.-at-.auckland.ac.nz) sent the message

Back to the Top

The following message was posted to: PharmPK

Rostam Namdari wrote:

> How do we evaluate the clinical/biological

> significance of drug accumulation based on PK data?

....

> Nick, regarding what I meant by drug accumulation, I

> was referring to use of AUC (simply comaring the AUC

> of the two cycles) or actual acummulation factor R =

> AUCss/AUC0-t (t= dosing intervals).

The accumulation ratio of concs at steady state to concs after the

first dose is most simply evaluated based on its magnitude. If the

ratio is close to 1 it means negligible accumulation; greater than 2

means at least 4 dosing intervals are required to approach steady state

and concs will be at least twice those seen after the first dose.

I can't think of any biological significance of the ratio. Any drug can

have any accumulation ratio -- it just depends on the dosing interval.

Clinical significance must take into account the time course of

beneficial and adverse effects. E.g. judge whether a loading dose would

be appropriate to get more rapid onset of benefit without unacceptable

adverse effects.

Even when a loading dose would seem like a good idea the occurrence of

initial adverse events can make it unwise. It can happen that tolerance

to adverse effects develops after the first few doses and better

overall results are obtained by not giving a loading dose e.g. oral

theophylline.

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

Want to post a follow-up message on this topic? If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Statistical Analysis for Repeated Dosing" as the subject

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)