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The following message was posted to: PharmPK
Hi, all
Is there anyone knows about any regulatory guideline/ published article for
validation strategies of Bioanalytical method(s) for GLP toxicokinetic
studies applicable to NCE's for regulatory submission (IND/NDA).
These studies are typically done in a variety of laboratory animal such as
mice, rat, dog and monkey covering wide dosage range and duration. This
ultimately boils down to bioanalytical challenges in terms of very wide
analytical range ( 2 to 4 log range) in levels of analyte and a variety of
biological matrices from different animal species. Some of specific my
questions in this regard are:
1- Due to small volumes of blood in mice, there are ethical issues in
sacrificing many mice for blank plasma for and using it for developing and
validating bioanalytical methods in mice plasma. Is it OK to use a method
fully validated in Human Plasma for analyzing mice plasma samples after a
brief cross validation with spiked mice samples?
2- Can one use two or more analytical methods: each with a linear analytical
calibration range of 1-2 log fold to analyze the samples of single study/
animal, if there are 3-4 log fold difference in plasma levels (as often
seen in a chronic toxicokinetic study)? Will it be acceptable to UDFDA?
3- Is there a guideline or well accepted norms for deciding outlires in PK
analysis and for selecting samples for repeat analysis in Toxicokinetic
study?
thanking you all in anticipation
Jyoti Paliwal Ph.D.
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The following message was posted to: PharmPK
I think the following Guidance issued by US FDA may be useful.
Full document may be found at
http://www.fda.gov/cder/guidance/ichs3a.pdf
Guideline for Industry Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity Studies
Summary of Analytical Section:
Analytical methods (3.10)
Integration of pharmacokinetics into toxicity testing implies early
development of analytical methods for which the choice of analytes and
matrices should be continually reviewed as information is gathered on
metabolism and species differences.
The analytical methods to be used in toxicokinetic studies should be
specific for the entity to be measured and of an adequate accuracy and
precision. The limit of quantification should be adequate for the
measurement of the range of concentrations anticipated to occur in the
generation of the toxicokinetic data.
The choice of analyte and the matrix to be assayed (biological fluids or
tissue) should be stated and possible interference by endogenous
components in each type of sample (from each species) should be
investigated. Plasma, serum or whole blood are normally the matrices of
choice for toxicokinetic studies.
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The following message was posted to: PharmPK
Dear Dr. Paliwal:
As far as the bioanalytical validation is concerned you don't have much
choice but to follow the USFDA guidance on bioanalytical method validation.
CFR categorically states that all Non-clincial animal studies (is human
animal is biggest question??) must be conducted according to GLP.
Bioanalytical methods work typically follow GLP.
Coming to your question on the ethical reasons of limited blood supply an
alternative can be first validate the intended analytical method in human
plasma keep this as a core master analytical method and then cross-validate
this method for other species biological matrix (which is typically a one
day add on mini validation) such as plasma, urine etc of different species.
In this way you don't end up having many analytical methods floating around
in your lab.
Hope this helps.
Prasad NV Tata, Ph.D.
Mallinckrodt, Inc.
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The following message was posted to: PharmPK
Jyoti,
I am told that the draft guidelines that were originally for Human PK
studies will now be applicable to all bioanalytical studies once finalized.
This comes form a statement made by Dr. Vishwanathan in March 2001.- Tom
H. Thomas Karnes Ph.D.
Professor and Director of Analytical Laboratories
Virginia Commonwealth University School of Pharmacy
Department of Pharmaceutics
PO Box 980533
410 N 12th Street
Richmond VA 23298-0533
Phone: 804 8283819
Fax : 804 8288359
E-mail : tom.karnes.-a-.vcu.edu
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The following message was posted to: PharmPK
Further to the regulatory points already commented by others I would like
to mention a commonly used procedure to cope with the large concentration
range observed in toxicokinetics. All samples which are above the
calibrated range can be diluted either with blank plasma or with water,
saline etc. provided that it was proven by quality control samples treated
in the same way that this procedure leads to accurate results.
Hope this helps,
Bernhard J. Ladstetter, Ph.D.
Institute of Pharmacokinetics and Metabolism
Merck KGaA
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A new FDA guidance for bioanalytical methods is currently in
preparation.
A draft has been published and there was much discussion at the Crystal
City Conference last year.
As a result of the Crystal City conference and responses from industry,
the draft guidance has been extensively revised.
Some recommendations did come out at the Crystal City Conference, and
you should look for the published report (I don't know if it's come out
yet). Remember points from Crystal City are open for discussion and ARE
NOT FDA POSITIONS.
1) The new guidance should be applicable to both human and non-human
samples. Consequently, whatever is currently available, e.g. old
guidances, 1990 crystal city conference recommendations, etc. could be
applied to both humans and non-human samples.
Partial cross validations as applied to certain conditions might be used
when appropriate, e.g. CSF samples and standard curve using another
biological matrix.
2) If two or more assays are used in a single study the overlapping
ranges should be cross validated.
3) Sponsor's should define a priori how they determine if a sample is an
outlier, as well as any samples for reanlysis.
Outliers should be reported (including derived metrics). However
sponsor's may also include metrics and summary statistics excluding
outliers. To allow evaluation of the data both ways.
Ronald E. Kavanagh. B.S. Pharm., Pharm.D., Ph.D.
Food & Drug Administration
Office of Clinical Pharmacology and Biopharmaceutics
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