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Hi All,
During some recent preclinical studies, I noticed a drug candidate
shows bioavailability greater than 1. This has been seen in rats and
monkeys with up to ~120%. And also it looks like: the lower the dose
is, the higher the bioavailability could be.
The bioavailability is SC vs. IV. A human antibody against a growth
factor was studied. The antibody level in plasma was determined by
ELISA.
Any suggestions on why a larger-than-one bioavailability is seen?
Thanks for any inputs.
Hao Pan
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Hao Pan,
I assume you are using the simple AUC ratio method for estimating
bioavailability. This requires the assumption that elimination is
first order.
The route dependent difference in apparent bioavailability could be
due to non-linear elimination e.g. if the concs are initially higher
after the SC dose then this may be saturating the elimination process
and leading to a disproportionate AUC increase.
The increasing bioavailability with dose suggests that bioavailability
itself is dose dependent e.g. due to saturable local metabolism or
changes in lymphatic transport. I think this has been well described
for big molecules like antibodies.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-at-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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The following message was posted to: PharmPK
Hello,
Concentrations should be initially lower after the SC administration
vs. IV dosing due to the absorption process (assuming similar IV and
SC doses are used). This >100% bioavailability could be the result of
FcRn which can act as the salvage receptor for antibodies. Initial
higher concentrations after the iv dose can saturate the recycling
process leading to higher lysosomal degradation. Lower concentrations
from the sc route may allow effective recycling and lower lysosomal
degradation. Thus, the route dependent difference in apparent
bioavailability could be due to a saturable salvage mechanism.
Some key points from Ref 1.
1. Page 2651: "The elimination of IgG is known to be concentration
dependent, where half-life decreases as a function of increasing serum
IgG concentrations.[36] In reviewing these characteristics of IgG
pharmacokinetics, Brambell et al.[37] proposed in 1964 that IgG may be
a substrate of a transport protein..."
2. Page 2649: "The extent of absorption may vary depending on the
extent of presystemic antibody degradation by proteolytic enzymes.
Proteolytic degradation may be saturable, leading to increases in
bioavailability with increasing doses of antibody"
Could the UB antibody PK-PD experts kindly comment.
Best wishes...Mahesh
Reference:
1: Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and
pharmacodynamics. J Pharm Sci. 2004 Nov;93(11):2645-68.
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Dear Hao,
Saturation of Enzyme Metabolism for your drug candidate may be the
cause of Decreased bioavailability with Increase in dose.
Regards,
Santosh Tata, BS (Pharm. Sci),
Bioanalytical Laboratory,
Clinsys Clinical Research Ltd,
C-46, Sector-62, NOIDA,
Uttar Pradesh, India.
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Hi Nick,
Thanks a lot for your reply.
I agree with the non-linear elimination possibility, however, within
the dose range we tested (highest > 10x lowest), all the elimination
phases show almost same slope and result in similar Ke. Plus, AUCinf
is in a very good linear relationship with dose. So it looks like the
elimination is linear, as least within each route.
The bioavailability I see is actually decreasing with dose. The
highest bioavailability (~120%) is seen with the lowest dose.
What's more, in case of saturated transporters in absorption, does it
really make bioavailability >1? The absorption is prolonged and curves
might become flat, but the plasma concentration should also fall since
not all drugs get absorbed. The drugs from extravascular routes have
no contribution to AUC untill after they are absorbed.
Thanks again.
Hao Pan
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