- On 22 Apr 2004 at 12:13:44, "VALERIA ZAPATA" (vzapata.at.osmotica.com.ar) sent the message
Hello everyone,

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How should a phase-I trial to assess dose-proportionality in five

different doses be arranged? Where can a find a model for this trial ?

How can a PK/PD trial be included in it?

Thank you.

Valeria Zapata

n: 54-11-4379-4200 int. 4099

Fax: 54-11-4379-4165 - On 22 Apr 2004 at 12:26:15, "Bonate, Peter" (pbonate.at.ilexonc.com) sent the message
Valeria,

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There are a couple of questions you need to ask here. How long is the

halflife of the drug. Is it so long that a cross-over study design is

prohibitive. If not, then that is how you want to run this trial - as a

randomized crossover. If not, then you need a parallel group design.

As for a model, do you mean a model for the experimental design, like

sample publications or do you mean model in the sense of how do you

analyze the data. If you mean the latter, the best way is usually a

power model (See Gough et al., Drug Information Journal 29; 1995;

1039-1048) using the modification of Smith et al. (Pharmaceutical

Research 17; 2000; 1278-1283). As for whether you need pk-pd, pd is not

usually part of the trial but I don't see why it couldn't be. The data

would just be more difficult to analyze but may be more informative if

you have a saturation of pd effect.

Good luck,

Pete Bonate - On 23 Apr 2004 at 17:28:58, (Kees.Bol.at.kinesis-pharma.com) sent the message
Dear Valeria,

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If you mean how a design of such a study should look like, than I can

give you information on a design that is often used as first dose in

man study (single dose escalation).

A relatively standard design for a SD escalation study is to study 6

increasing dose levels in two alternating panels of 9 subjects (total n

= 18). Thus each subject is studied in three times.

At each dose level 6 subjects will receive active drug substance and 3

subjects will receive placebo.

Dose-propotionality can be assessed graphically or statistically.

Graphically can be best done by making dose-normalized plots of the

relevant PK parameters. The overall mean of the dose-normalized

parameter can be plotted as horizontal line in de plot. Deviations

below or above the line indicate deviations from dose-proportionality.

Some statistical evaluations have already be mentioned by Peter Bonate.

I would like to add a linear mixed effect modeling procedure on the

dose-normalized parameters in which you have dose as fixed effect. With

contrasts you can make pair-wise comparisons between the different dose

levels and explore statistical significant differences.

The placebo subjects allow you to collect baseline information on the

incidence of AEs (if you like to do PK/PD on that) or on the

variability of certain pharmacodynamic measures/biomarkers of interest.

Best regards,

Kees

Kees Bol, PhD

Director Clinical Research

Kinesis Holding

Consultant in Drug Development

Lage Mosten 29

4822 NK Breda

The Netherlands

tel: +31 (0) 76 54 80 621

fax: +31 (0) 76 54 21 777

www.kinesis-pharma.com - On 24 Apr 2004 at 02:15:01, "Clerk Maxwell" (clerkmaxwell.-a-.hotmail.com) sent the message
Nice post by Kees. The plot I like for evaluation of linearity of a

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relevant parameter (e.g., clearance) is as follows (for clearance, but

it can be modified for Cmax, etc.):

CL(mL/min/kg) vs. Dose (mg/kg). You can then test the slope to see if

it is statistically significantly different from zero. Also, visual

inspection simply illustrates non-linearities, even those which don't

achieve statistical significance. For example, if the plot slopes

downward, this would indicate CL is reduced as dose increases. One can

also do the fancy statistical tests, but this is simple and reliable,

and you don't need to be a statistician to apply or understand it. Of

course, I expect the "hard-core" statisticans may wish to apply more

vigorous methods, and that's OK with me. Its just that this is simple

and easy to interpret, especially when there are outliers. Best

wishes. Harold.

Harold Boxenbaum, Ph.D.

Arishel Inc. (Consulting)

Pharmacokinetic n Pharmaceutical n Medical n Biotechnology n

Nutraceutical

14621 Settlers Landing Way

North Potomac, MD 20878-4305

Phone: (301) 424-2806

Fax: (301) 424-8563

E-Mail: harold.-a-.arishel.com

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