- On 8 Aug 2005 at 17:29:32, "Letendre, Laura" (Laura.Letendre.at.Merial.com) sent the message

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I am working on a sample size calculation for a two period cross-over

design using nQuery Advisor. The program asks for the CV. The CV I

want is the within subject CV which can be estimated from a crossover

pilot study. This is calculated using the residual (within-subject

variance) from proc Mixed in SAS on Ln transformed data. I=92m told

that the CV should be calculated by dividing the residual variance by

the square root of two. Does anyone know if this is correct? If so

where does the square root of 2 come from? Does anyone know any good

references for this - I already have the papers with tables but I am

trying to understand the procedure used here.

Also, an easier question:

I am designing a BE study with a two period crossover design. The

half-life of the drug is 3 days and the Tmax is 2 days. The washout

period I want is 10x the terminal half-life or 30 days. Would I give

the second period dose on day 32, 30 days after Cmax? My question is

when does the washout period begin - at Cmax, at t=0?

Thanks!

Laura - On 9 Aug 2005 at 09:06:50, "Vinay Hk" (vinay.hk.at.ranbaxy.com) sent the message

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The following message was posted to: PharmPK

Dear Laura

The formula for calculating the sample size is sqrt(exp(residual

variance)-1). This is the formula that I use, proposed by Diletti et

al 1991. Ref- Sample size determination for bioequivalence

assessment by means of CI. Int Journal of Clinical Pharmacology,

Therapy and Tox, 29; No.1 1991 (1-8). This paper may clarify all

your doubts.

Washout : It does not start from Tmax. It starts from t=0.

With regards

Vinay - On 9 Aug 2005 at 09:56:52, mallikarjunard.-a-.drreddys.com sent the message

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Dear Laura

My answer to your question on washout period.

Washout period ideally considered as period between the dosing

timings in two periods. If you are dosing on Day 1 in period I and

dosing in period II can be on Day 31 keeping 30 days washout period.

Thanks

D Mallikarjuna Rao

[I updated the PharmPK archive (and CD) over the weekend - db] - On 9 Aug 2005 at 17:55:06, radhakrishnav.at.drreddys.com sent the message

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Dear Laura Letendre,

1. The intrasubject variability is the square root of the mean squared

error from the crossover ANOVA computed using the natural log scale.

2. The washout period of a drug is calculated from the half-life, you

can

dose second period on day 30.

With Regards,

V.Radhakrishna

Clinical Pharmacology and Pharmacokinetics - On 9 Aug 2005 at 09:32:57, DDubins.at.allied-research.com sent the message

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Hey Laura, the reality is that by 10 half-lives there will be less

than 0.1% of the drug left, so a few days probably won't end up

making any difference. However, if we can envision a modified release

drug with a Tmax of 1 day with a flat profile but a half-life of 2

hours, we would run into difficulties if we start the washout clock

at t=0. In this case, 10 half-lives after t=0 gets you to 20 hours,

not even passing the Tmax. So in principle, I would start the washout

clock at Tmax to be conservative (realizing that in most cases it

shouldn't make much of a difference considering the inter-individual

variability of PK parameters). One more comment about washout, it is

usually preferable to run each period on the same day of the week and

the same time of day to normalize for circadian effects, so if you're

debating between 30 and 32 days washout, perhaps you could consider

either 28 days or 35 days after t=0.

-Dave - On 9 Aug 2005 at 12:42:21, "Edmond B. Edwards, Ph.D." (editr.at.sympatico.ca) sent the message

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Hello Laura,

By now you've heard about all you want to hear - and here's some

more: if you're designing your washout period for the Regulatory

Agencies, please note that 5 half-lives are usually sufficient to

reach the limit of quantitation (LOQ) of most analytical methods, so

you might want to estimate if (15 +2) days will result in samples

that are below the LOQ. Also, the last time I checked, the FDA will

allow a carry-over if it is less than 5% of the Cmax in the next

period. Hope this encourages you to select a shorter washout time,

since one of the concepts behind the cross-over design is a similar

population between periods and 30 days might just compromise this

implicit assumption.

Good Luck.

Edmond B. Edwards, Ph.D.

EDIT Research - On 9 Aug 2005 at 13:52:07, "Nageshwar R. Thudi" (nageshwar.thudi.-at-.ranbaxy.com) sent the message

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HI Laura,

I do agree with what Dr Edmonds says, if you really want to shorten the

washout period. But if you don't want to invite any risks regarding

carryover in predose samples of next period I suggest you to go for more

than 5 half life's but less than 4 weeks.

Hope this will help you,

Nageshwar - On 10 Aug 2005 at 10:08:24, "Mitesh Gandhi" (miteshgandhi.at.alembic.co.in) sent the message

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Dear Laura

Useful articles for sample size calculations:

1. International Journal of Clinical Pharmacology, Therapy and

Toxicology:Vol 30, Suppl No. 1-1992(ppS51-58).

2. Statistics in Medicine, 2004; 23: 1921-1986 'Tutorial in

biostatistics -

Sample sizes for clinical trials with normal data'

Washout period :

Washout period is a gap in between two dosing. Starts at t = 0.

Regards

Mitesh Gandhi - On 10 Aug 2005 at 19:06:06, "Heuvel, M.W. van den (Michiel)" (michiel.vandenheuvel.-at-.organon.com) sent the message

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The following message was posted to: PharmPK

Dear Laura,

I guess you are using the older version of nQuery (e.g. V3.0), where

programs MTE0 and MTE1 can be used for sample size calculations in

equivalence settings both for two-group (i.e. parallel) designs and for

cross-over designs. In both cases the same formulae are used without the

program knowing which situation it is dealing with.

In case of a two-group parallel test the number of subjects per parallel

group (n) is calculated and assuming equal n's the total sample size

will be 2n. The variance of difference in treatment means will be:

VAR(diff) = VARe * (1/n + 1/n) = VARe * 2/n.

In case of a two-way cross-over design the number of subjects per

sequence group (n) is calculated and the total number of subjects will

also be 2n. The variance of difference in treatment means will be here:

VAR(diff) = VARe * 1/4 * (2/n + 2/n) = VARe * 1/n (using a cross-over

model).

So the variance for the cross-over situation should be a factor two

lower than in the two-group situation. This factor 2 difference in

variance corresponds to a factor square root of two in standard

deviation (or CV).

In the newest version V5.0 you now have separate programs for the

two-group tests and the cross-over tests, which makes life somewhat

easier.

Hope this helps you.

Michiel van den Heuvel

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