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Dear all,
Does anyone know of possible problems that may arise due to unequal
length of washouts between periods? As per guidelines, washout
periods should be at least five half lives, would there be bias if
say for a 3X3 crossover design, the washout between period 1 and
period 2 is five half lives and between period 2 and period 3 its ten
half lives.
Your feedback would be much appreciated.
Regards,
Nav
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It would depend on the nature and variability of the drug; if there
are slow metabolizers, you could potentially run into problems. As
general practice you should consider equal washout times to avoid
period differences. Why shoot yourself in the foot before you even
start? Although the FDA guidelines specify 5 half-lives as a suitable
washout period, the TPD guidelines recommend at least 10 half-lives.
Just some food for thought.
Dave Dubins B.A.Sc., Ph.D.
PK Scientist
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Dear Mr.Navdeep,
I hope there no question of bias in regard to washout between two
periods.
The difference you may experience in between to different washouts is
the
period and sequence effects. Since this a cross over study the sequence
effect is not a question. The period effect you may experience or not,
may
be due to inadequate washout in between period1 and period2.
With Regards,
V.Radhakrishna
Clinical Pharmacology and Pharmacokinetics
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The following message was posted to: PharmPK
Dear Navdeep,
As fact a drug takes ten half lives to completely get eliminated from
body.
Washout period of 5 half lives will lead to predose concentration on
comencement of period 2. Thus, the AUC we obtain will change. There
can't be head to head comparison of PK/PD effect of period 2 with
other periods.
Solution: in such cases the AUC of period 2 has to be corrected.
Concentration (0 min)/Kelimination (period 1) = AUCt-infinity
This area has to be substracted from total AUC0-infinity (period 2)to
give corrected AUCin period 2
Further, confirm if it is acceptable as per guidelines(regulatory)or not
Gurpreet Saini
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The following message was posted to: PharmPK
Dear Navdeep:
Washout between periods is intended to avoid any carry-over of the prior
treatment. Usually washout period is intended to minimize the pre-dose
concentrations in pharmacokinetic samples and LOQ of your analytical
method
determine the length of wash out period, in other words if you keep in
sufficient washout you may see pre-dose concentrations, messing
calculations
of subsequent treatments. A place where I can think you can justify
different durations of wash out is for a drug that is undergoes auto
induction or auto inhibition requiring varying durations of washout
and even
different blood draw schemes.
Having said all these I think you have to clearly justify this in your
protocol.
Hope this helps.
Prasad Tata
Saint Louis, MO
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The following message was posted to: PharmPK
Gurpreet Saini wrote:
>
> As fact a drug takes ten half lives to completely get eliminated from
> body.
This 'fact' is an approximation. If you want to believe a first-order
elimination model then it takes an infinite amount of time to
completely eliminate all the drug. In practice 5 half-lives should be
good enough even for the most compulsively obsessive regulator.
--
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/
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The following message was posted to: PharmPK
Dear Gurpreet,
you wrote:
>As fact a drug takes ten half lives to completely get eliminated from
>body.
>
Ok, if you are talking about 'facts':
after 5 half lives 96.88% are eliminated
after 10 half lives 99.90% are eliminated
A drug /never/ gets 'completely' eliminated, since we apply the concept
of half lives to a stochastic process. The last molecule remaining in
the
body may be eliminated 1 half live after the previous one - or in the
next second - or never ;-)
How many half lives we consider suitable for our model is just a
convention.
In BE studies I would regard washout periods of 5 half lives as
'conventional', 7 half lives as wary, and 10 half lives as overcautious.
>Washout period of 5 half lives will lead to predose concentration on
>comencement of period 2. Thus, the AUC we obtain will change. There
>can't be head to head comparison of PK/PD effect of period 2 with
>other periods.
>
If you 'see' pre dose concentrations after 5 half lives, maybe you
invested to much money pushing the limits of your bioanalytical
method ;-)
Normally 5% of Cmax are fine to cover >80% of AUCinf.
>Solution: in such cases the AUC of period 2 has to be corrected.
>
>Concentration (0 min)/Kelimination (period 1) =UCt-infinity
>
>This area has to be substracted from total AUC0-infinity (period 2)to
>give corrected AUCin period 2
>
>Further, confirm if it is acceptable as per guidelines(regulatory)
or not
>
IMHO this procedure is not acceptable according to *any* regulatory
guideline.
Incorporating (and testing) a carry-over term in the statistical model
for BE is obsolete since 1989 (P.R. Freeman; The Performance of the
Two-Stage
Analysis of Two-Treatment, Two-Period Crossover Trials.
Statistics in Medicine 8, 1421-1432.)
best regards
Helmut
--
Helmut Schuetz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
http://BEBAC.at
Bioequivalence/Bioavailability Forum at http://forum.bebac.at
http://www.goldmark.org/netrants/no-word/attach.html
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The following message was posted to: PharmPK
Dear Navdeep:
Most colleagues are pointing to carry-over effect with
regard to drug residues (i.e., pre-dose
concentrations), which of course is important. You
also need to consider the pharmacology of your drug,
target organs and expected toxicities and account for
pharmacological/toxicological recovery. The drug may
well be cleared from the body (say within a week or
so) but there are some transient effects, which may
influence the drug disposition, and take longer than a
week to recover.
Rostam
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Dear Navdeep,
In general the treatment with the greatest half live determines the
lenghth of the washout period. In a crossover design, this treatment
will be given in each period. Therefore the washout between study
periods should be the same for crossover designs.
Peter
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Nick Holford wrote:
> This 'fact' is an approximation. If you want to believe a first-order
> elimination model then it takes an infinite amount of time to
> completely eliminate all the drug.
This is again an approximation. Even under the assumption of a first-
order elimination model you can say:
At the time, at which the total amount of drug in the body is below
the molecular weight, the drug is completely eliminated. And this
time is finite for a first-order elimination model.
Peter
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The following message was posted to: PharmPK
In fact, when the total amount of drug in the body equals
the molecular weight that means there is a mole of drug in the body,
6.022x10^23 molecules of it. So the answer for a suspected carry-over
effect shouldn't be perhaps waiting until the very last molecule is
eliminated. Who said that drugs are all eliminated by first order
processes?
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.-at-.bos.mcphs.edu
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>In fact, when the total amount of drug in the body equals
>the molecular weight that means there is a mole of drug in the body,
Most drug doses are well under a mole. Although one mole sounds like
a small number, if the molecular weight of a drug (say for example,
ciprofloxacin) is around 390 g/mol, then one mole of ciprofloxacin
will weigh about 390 g (corresponding to Avogadro's number of
molecules). If you were to ingest a mole of ciprofloxacin, this would
amount to eating about 8 chocolate bars worth. So it would be very
unlikely for someone to have to ingest an entire mole of drug, as
most drugs have fairly large molecular weights. Since elimination for
most drugs can be modeled as a first, second (or even third?) order
exponential decay, large amounts can decay quite rapidly and it is
the rate of elimination, not the initial drug amount, that ends up
being more important in estimating a washout period. I am reminded of
lottery winners, who within a few short years are back where they
started because they are unable to manage their money.
Dave Dubins
PK Scientist
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The following message was posted to: PharmPK
Navdeep Randhawa wrote:
> Does anyone know of possible problems that may arise due to unequal
length of washouts between periods?
However, the initial thread by Navdeed reminds me that some causes for
a significant carry-over effect may not be directly related to
elimination half-lives and actual amounts of drug in the body. I'm
thinking more along pharmacodynamic causes such as one that I remember
where short term tolerance was detected and subjects at the second
period had different metabolic characteristics.
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA=A0 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.aaa.bos.mcphs.edu
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