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I have data following SC and IV dosing in rats (n=6 each route), in
which the AUC following SC dosing was over 2-fold higher than the AUC
following IV dosing (the same dose amount was administered via each
route). Visual examination of the concentration-time profile
indicates the compound is rapidly distributed and appears to follow
tri-exponential decay following IV dosing. Mean concentrations fall
by a factor of 100 within ~30 minutes after dosing. This pattern was
consistent across all 6 animals.
The concentration profile following SC dosing was more variable at
early time points. Some animals displayed rapid absorption (tmax 2.5
minutes) followed by quick initial distribution; other animals
displayed slower absorption, with less pronounced distribution. In
all animals, a prolonged terminal elimination phase is apparent with
SC dosing (similar to IV).
Protein binding is ~50% in dogs and humans (no data available in
rat). Previous tissue distribution studies with 3H-labeled compound
in rat (IV and PO) showed several tissues had a higher level of
radioactivity than blood, indicating a large volume of distribution.
The main route of elimination is renal (~45% of an IV dose, primarily
recovered as parent drug). Excretion into bile (~25% of an IV dose,
primarily as parent drug) also occurs.
My question is: how can the SC dose have >100% bioavailability
relative to IV? Is this a distribution phenomenon? I appreciate any
advice regarding the best way to explain these results to non-PKists.
Best regards,
Joi Dunbar
Alkermes, Inc.
joi.dunbar.-at-.alkermes.com
[Could the protein binding be saturable (this could look like multi-
compartment kinetics after IV)? Any non-linearity in the kinetics? - db]
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The following message was posted to: PharmPK
Please remember that after an IV dose there is still first pass
elimination by the lung. For some drugs, this removal process is
quantitatively important. The true reference should be intra-arterial
injection for absolute bioavailability. Grant Wilkinson and colleagues
wrote a nice review on this a long time ago that I believe was
published in
Pharmacological Reviews.
Dr. Daniel Sitar
Professor and Head, Pharmacology and Therapeutics
Professor, Internal Medicine (Clinical Pharmacology)
Tel: 204-789-3532 FAX: 204-789-3932
Email: sitar.aaa.cc.umanitoba.ca
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The following message was posted to: PharmPK
Dear Joi,
Although very rare, there have been cases during the investigational
drug
development process where AUC following IV dosing is lower than the AUC
following other routes (e.g., Po, rectal, SC etc.). There may be several
explanations of this anomaly including, water solubility of the drug,
salt
form, lipophilicity and lung first pass metabolism.
Thanks,
Masood Bhatti, Ph.D.
Director, Clinical Operations
Biovail Contract Research
Toronto, Canada
416-752-3636 Ex.381
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