Back to the Top
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
Back to the Top
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
Back to the Top
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]
Back to the Top
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
Back to the Top
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
Back to the Top
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
Back to the Top
The following message was posted to: PharmPK
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
Back to the Top
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
Back to the Top
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
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)