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The following message was posted to: PharmPK
Hi:
One of our drugs is an ester and gets converted to an active metabolite,
an acid. Both the parent and the metabolite is observed in the plasma
when administered PO and IV. When bioavailability (F) is calculated,
should we calculate it based on the AUC of only the parent or sum of
both the parent and the metabolite in plasma?
Thanks
Ananda
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The following message was posted to: PharmPK
Hello, I'm new to the list serve, but it seems to me that you would
want to
base it on the parent compound only. The AUC of the metabolite is not
dependent on route of administration directly, but on metabolism of the
parent compound. The metabolite is not present in the drug formulation,
therefore is not absorbed from the gut. Hence bioavailability does not
apply.
Michael Neely, MD
Assistant Professor of Pediatrics
Division of Pediatric Infectious Diseases
Laboratory of Applied Pharmacokinetics
Keck School of Medicine
University of Southern California
1640 Marengo St., Suite 300
Los Angeles, CA 90033
Tel: (323) 226-5068
Fax: (323) 226-8362
Voicemail: (323) 226-2330
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The following message was posted to: PharmPK
It depends on whether the parent compound is active or not. If not, the
metabolite AUC should be calculated. The metabolite AUC IS dependent on
the parent compound bioavailability.
İlbeyi Ağabeyoğlu
Proffessor of Pharmaceutical Technology
Dept.of Pharmaceutical Technology
Faculty of Pharmacy
Gazi University
Ankara, Turkey.
ilbeyi.aaa.tr.net
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The following message was posted to: PharmPK
Hi,
The answer to the question depends on the type/PK properties of drug and
metabolite.
Indeed, the metabolite AUC IS NOT ALWAYS dependent on parent compound
bioavailability. For example, in case the parent compound is already
extensively metabolised in the gut (for example by non-enzymatic
hydrolysis
of an ester), it might be that some of the metabolite (even if not
present
initially in the formulation) is directly absorbed as itself from the
gut.
This would result in a poor apparent parent drug bioavailability,
although
an actual good plasma exposure to the metabolite can be observed.
In this case, it would be useful to calculate not only parent drug AUC,
but
also metabolite AUC and eventually the sum of parent compound and
metabolite
AUC to estimate a "global drug exposure".
However, results based on the sum of parent compound and metabolite AUC
should be interpreted with caution considering that PK properties (e.g.
clearance, volume of distribution) of parent compound and metabolite
might
be different, that other major active metabolites might be not yet
identified, and in case of a non-linear kinetics for one or both
compounds.
There is an interesting paper from the FDA discussing this matter with
respect to bioequivalence issues :
Int J Clin Pharmacol Ther 1998 Oct;36(10):540-4 Links
Assessment of metabolites in bioequivalence studies: should
bioequivalence
criteria be applied on the sum of parent compound and metabolite?
Mahmood I.
Office of Clinical Pharmacology and Biopharmaceutics, Division of
Pharmaceutical Evaluation I., Food and Drug Administration, Rockville,
MD
20852, USA.
OBJECTIVES: The objective of this study was to demonstrate the impact
of the
sum of parent compound and metabolite in bioequivalence assessment.
METHODS:
Four drugs with active metabolite were selected to assess
bioequivalence.
Bioequivalence criteria of 80 - 125% were applied to the parent
compound,
the metabolite, and the sum of parent compound and metabolite. RESULTS:
The
results indicated that the application of 80 - 125% bioequivalence
criteria
to the sum of parent compound and metabolite might be misleading.
CONCLUSION: The 90% confidence interval should be applied separately to
the
parent compound and each metabolite.
Another paper (also discussed in the FDA paper) :
Int J Clin Pharmacol Ther 1996 Jan;34(1):32-7 Related Articles,
Links
Bioequivalence study of alpha-dihydroergocryptine: utility of metabolite
evaluation.
Ezan E, Ardouin T, Delhotal Landes B, Flouvat B, Hanslik T, Legeai JM,
Grognet JM.
CEA, Service de Pharmacologie et d'Immunologie, Gif-sur-Yvette, France.
Metabolite assessment is an open question in bioequivalence studies. In
situations of low absorption, high first-pass metabolism, and
intrasubject
variability, metabolites may reflect absorption more adequately than the
parent drug, and their determination may help decision-making in
bioequivalence issues. Treating alpha-dihydroergocryptine (DHECT) as a
model, we used both unchanged DHECT and a pool of DHECT metabolites to
evaluate the bioequivalence of 2 oral DHECT formulations (reference-R
and
test-T) in 12 subjects. DHECT and its metabolites were immunoassayed.
There
was no difference between the 2 formulations in terms of the
AUC0-infinity
(area under the curve) values determined from unchanged DHECT or DHECT
with
metabolites profiles: 572 +/- 490 pg/ml.h (R) and 442 +/- 276 pg/ml.h
(T)
for unchanged DHECT, and 7,141 +/- 2,936 pg/ml.h (R) and 6,941 +/- 1,462
pg/ml.h (R) for DHECT with metabolites. Confidence intervals were
within the
ranges 0.8-1.25 (AUC0-infinity) and 0.7-1.43 (Cmax) for DHECT with
metabolites but not for unchanged DHECT. This study describes a
particular
case where only measurements on the basis of the metabolites can
justify the
assumption of bioequivalence.
Best regards,
VaNic
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The following message was posted to: PharmPK
Hi Ananda,
according to me you have to take into account both the parent and the
metabolite. In fact the acid form is also a marker of the ester
absorption
through the intestinal membrane.
IV is your reference and shows some acid in the plasma as well. This
means
that your reference drug amount is acid+ester.
So you cannot ignore this and you should really consider the sum of
acid+ester for your calculation.
Hope this helps,
Frederic
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The following message was posted to: PharmPK
Dear Amanda,
Thanks for the interesting question.
It may well be the case that the route of administration of parent
determines the extent of metabolism. For example, if there is
significant
metabolism in gut wall after po administration, the levels of metabolite
after po may be greater than those seen after iv administration of
parent
(apparent BA for metabolite in excess of 100%).
If you simply concentrate on parent, this will only be limited
information
(but you do need to make this calculation). I presume that the parent
is
pharmacologically inactive (acid and esters have very different
properties
and it’s likely you’ve developed this compound as a prodrug so that it
may
be administered po in the clinic?).
In order to get the information regarding the bioavailability of the
metabolite, in my view you would need to dose the metabolite iv, and
compare the AUC gained from this study with the AUC of metabolite
following
po parent compound (correcting for any difference in dose level in
terms of
moles). This allows you to estimate the po bioavailability (including
absorption and metabolism) for your active component in terms of maximal
available in dose.
Hope this helps,
Dave
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