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What are the main factors to have >100% bioavailability (F) for an
NCE under development by oral route at a dose higher than the tested
i.v dose. For eg: NCE has bioavailability of 100%, when tested by
i.v and oral at 3 mg/kg, but because of formulation limitation if we
can not deliver 10 mg/kg dose by i.v, if we used AUC0-inf of i.v dose
to calculate F at 10 and 30 mg/kg, if it comes more than 100%, what
could be the reason(s). Is it mainly due to saturated metabolism or
by any other reason? By oral route you see the more than
proportional increase in AUC but Cmax is proportional to doses
administered (3, 10 and 30 mg/kg). We have used different set of
animals for each study. Method of analysis is HPLC and there no much
deviation in estimating the NCE concentration by HPLC.
Thanks
Ramesh
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Dear Ramesh,
In the present day scenario, poor oral bioavailability (BA) has been an
industry wide problem owing to increasingly lipophilic compounds (with
poor aqueous solubility) emerging from drug discovery programs. In this
scenario, your issue of greater than 100% BA, although requires probing,
is something that everyone loves to have!
While there could be various different reasons for >100% oral BA, I
guess it is important to confirm that the doses administered are what
you actually intended before probing too much into this issue. You may
have already looked into this, but it is worth double checking the
actual concentration of formulation, volume of dose administered and, if
you administer aliquot from a bulk formulation, the homogeneity of
formulation and hence the uniformity of the doses administered. If none
of these are issues and if the BA is significantly higher than 100% and
show increasing trend with increasing oral dose, then the issue is worth
probing!
As the oral BA of a compound depends on the extent of absorption,
distribution and elimination, it is important to know which of these
processes are responsible for >100% BA. From the information given I
guess there are no issues with respect to 'absorption' (as oral BA is
100% at 3 mg/kg) and solubility (in which case you should see decreased
BA with increase in the oral dose). Also, the fact that the Cmax is dose
proportional also suggests that absorption is not solubility limited
and, probably, no changes in the extent of 'distribution'. What remains
is the 'elimination', the major determinants of which are metabolism
(liver/intestinal), biliary excretion (parent or conjugated metabolite)
and excretion of the intact compound into the urine along with any
involvement of transporters in these processes.
Saturation of intestinal efflux/metabolism at higher doses could some
times enhance oral BA, but as you have BA of 100% at the lowest oral
dose, I imagine, this may not be an issue in your case. I am not sure
how big your NCE compound to be a candidate for excretion into bile
'neat' and if there are any metabolically labile groups for direct Phase
II conjugation making it a substrate for biliary transporters. If the
biliary excretion of the compound through bile is high, then this could
lead to significant entero-hepatic recirculation (EHR). If this is the
case this could lead to repeated absorption of the same drug leading to
enhanced AUC and hence %BA (Is 100% BA at lowest oral dose due to the
EHR rather than complete absorption!?) Alternatively, if the NCE is a
substrate for sinusoidal (blood side) uptake transporters in the liver,
saturation of this process at high concentration would lower entry into
hepatocyte and therefore lower liver metabolism. If this is the case
plasma concentration of the parent (metabolite to parent ratio
decreases) would increase which again result in higher %BA. However, if
the compound is substrate of canalicular (bile side) efflux transporters
and if this process saturates at high concentrations, the resulting
effect would depend on the extent of metabolism and its interplay with
efflux which could result in all possible observations (i.e. no effect,
decrease or increase in the AUC of parent). Finally, if the excretion
into urine is an active process, saturation of this at higher doses
could result in more than proportional increase in AUC. If this is the
case and if you have monitored urinary excretion of the parent, the % of
dose excreted into urine should decrease with increasing dose.
So, there are numerous reasons for such an observation and the interplay
of different events makes things even more complex. In such a scenario
it is important not to jump to any conclusions based on a certain
observation as it is possible that the particular observation could be a
net effect of 2 or more opposing events. The best thing to do in such
situations is to monitor the mass balance and see where the compound is
going and if most of the dose administered is accountable. It is not
possible to draw definitive conclusions if a major part of the dose is
unaccountable!
Hope this longwinded response answers your query.
Cheers!
Kasiram.
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Hi Ramesh,
what are the formulations used for IV (3mg/kg) and PO (3, 10 and 30
mg/kg) dosing?
Best regards,
Frederic
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Another possible reason for the increased bioavailability at higher dose
is the increased pharmacological activity of the test compound at higher
doses.
e.g. reduced blood supply to the eliminating organs (liver and kidney)
at higher doses results in reduced clearance and increased
bioavailability.
Regards,
Jayasagar Gundu
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