Back to the Top
A bioequivalence study in patients with cancer is planned with
intravenous Doxil as reference.
If the dose of test or reference needs to be reduced in the second
period, are there any guidelines on dose adjustment?
Or should that patient be excluded from the analysis?
Does anyone have any experience in IV bioequivalence where doses were
not identical?
Thanks for any advice.
Charlie
Charlie Brindley, KinetAssist
Back to the Top
Hi Charlie
when you calculate the BA, just use AUC or Cmax normalized to the dose.
In this case you are getting a comaprison of the parameter such as AUC
(mg. hr/ml per gm drug dose)
hope this helps
Noha
Back to the Top
The following message was posted to: PharmPK
The doxil dose reductions should be dictated by the treatment
protocol/algorithm. The patient does not need to be excluded from the
analysis. Many bioequivalence studies have different doses used. This
should not be a problem. This approach should be taken into account in
the bioequivalence equations you use.
Back to the Top
The following message was posted to: PharmPK
Hello Charlie,
Im a bit of a newbie to the area of Iv pk with only 2 years experience
of same and so may not be all inclusive here in this reply :
It depends :
On the statistical analysis design, the size of the study and hence the
influence of 1 subjects data on the overall result. Technically if a
subject does not complete the dose regimen as per the SAP the subject may
not be considered fully crossed over w.r.t. The trial design - if it's a
2 way crossover study that is. The permutations are considerable. In
short, the subject data may likely be excluded from the statistical
analysis but may/not remain in the summary data as current regulation
require the inclusion of All trial data, the good, the bad and the
influential.
Best of luck.
Kevin
Back to the Top
Hello,
It seems from your message that both the test and reference products
will be administered intravenously.
If this is the case, then a bioequivalence trial will be unable to
assess 'relative bioavailability'.
An i.v. infusion has 100% bioavailability by definition, so when
comparing the usual PK metrics for two i.v. infusions - reference or
test - the ratio must, or should be - close to 100%. (within the bounds
of experimental error). In practice, the actual ratios will depend of
the relative strengths of the stock solutions for test and reference
formulations, but the theoretical relative bioavailability remains at
100%.
You might want to question the ethics of putting a cancer patient
through this process when the results will not be able to assess the
purpose of the bioequivalence process.
However, if you meant to imply that the test drug is in one form and the
reference drug in another (i.v.), then you should check with the
appropriate Regulatory Agency. In most guidances, the test and
reference drug must be in the same galenic form (i.e. tablet vs. tablet,
sc injection vs. sc injection, etc.).
Under these circumstances, the Regulatory Agency might not accept the
results without prior approval of the protocol.
Best Wishes,
Edmond Edwards,
EDIT Research
Back to the Top
The following message was posted to: PharmPK
Hi Edmond et al.
Thank you for your responses.
The assessment of bioequivalence of a generic pegylated liposome of
doxorubicin hydrochloride with Doxil is required by the FDA even though
administration is intravenous.
Measurement of encapsulated and un-encapsulated doxorubicin needs to be
measured in plasma of cancer patients.
I'm assuming that the dose level (50 mg/m2), recommended by the FDA, is well
tolerated by patients so hopefully there will not be a dose reduction.
However, the clinician had concerns on toxicity and I was checking if anyone
had experience of dose reduction in bioequivalence assessment.
Charlie
Back to the Top
Thanks Charlie
Given the good predictive nature of lab tests on the performance of
liposomes, I'm surprised that a bio-equivalencel trial is also
necessary. Does anyone have evidence that the lab tests are not as
predictive as I assume? If there isn't any such evidence perhaps we
can avoid having to do unwanted trials in cancer patients.
Incidentally, if the preparation does not work it would soon be evident
in the patient's white cell count, so it seems to me that defining the
exact Pk profile is academic.
Andrew
Back to the Top
The following message was posted to: PharmPK
Hi Charlie,
Based on my understanding to your question, considering the IV
administration of the drug, the parameters that you are interested in
studying will not be influenced by changing the dose, All what you have
to do is to normalize for the new dose, so I will not suggest that you
exclude this subject's data from the analysis.
Good Luck
Ahmed Abdelhadi
Back to the Top
The following message was posted to: PharmPK
Hi Andrew,
You make a good point and, indeed, in vitro bioequivalence of generic
"Doxil" is also required by FDA.
Is vitro bioequivalence sufficient?
Clearly, we should avoid unnecessary exposure of drugs to cancer
patients.
Charlie
Back to the Top
The following message was posted to: PharmPK
Hi Charley,
I have recently developed a protocol for a DDI study in cancer patients,
where you face the same problem that in the second period the dose of
the chemo may need to be reduced. We set a limit to the dose reduction
of 5%, as the dose reduction could be due to say liver or renal function
going down which might affect exposure. Another thing is the volume of
the IV fluid which may be affected by a dose reduction, you would need
to make sure that volume is the same throughout; this applies in any
case, also of pre-dose IV fluid load which is applied for some chemo's.
You have to ask yourself the question whether or not a (slightly) lower
dose will affect distribution, relative amount of encapsulated and
un-encapsulated doxorubicin, i.e., can you think of any PK measure that
will be affected that cannot be corrected for by normalizing for dose.
The most important question is probably why was the dose reduced...
Regards,
Frieda
frieda.ebes.-a-.incresearch.com | www.incresearch.com | INC Research(r)
Back to the Top
Hello Charlie,
Thank you for your update - it certainly puts a few issues in a
reasonable perspective.
I can now understand why the FDA would be interested in a bioequivalence
study - presumably encapsulation is of little consequence. Could this
have been settled in an in vitro analysis just as well?
If you're using a crossover design for bioequivalence, perhaps using the
same reduced dose for both sequences would still give you a valid ratio.
Otherwise, the usual way is to do the analysis with and without dose
normalization. In most cases the outcome is the same if there are
sufficient numbers of patients.
All the Best,
Edmond
Back to the Top
The following message was posted to: PharmPK
Hi Frieda,
Thank you for your very helpful comments. With a limit on dose reduction
of 5%, there shouldn't be a problem with dose-adjustment of PK parameters.
That's a nice point about why there was a need for dose reduction,
especially if it was associated predominantly with the generic
comparator.
Charlie
Back to the Top
We need to exclude the subject from analysis
Back to the Top
Dear Charlie Brindley,
If you expect that the patients will be receiving different doses before
initiation of the study, dose should be included in the statistical
model. Correction for differing dosing regimens by dose-normalization is
generally not recommended by FDA.
See the following FDA individual product Bioequivalence Guidances for
other cytotoxic drugs regarding FDA's thinking on Dose-normalilzation.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm083276.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM220118.pdf
If the Investigator feels that the dose need to be reduced due to
toxicity for that particular patient, we need to exclude that subject
from the analysis.
Regards,
Dr.S.Gunasakaran, MD
Head - Clinical Research & Medical Affairs,
Azidus Clinical Research Organization, India
|
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 "Bioequivalence in cancer patients" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)