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We have a compound having high blood/plasma ratio when dosed orally in vivo in preclinical species.
The blood/plasma ratio was found to be as high as ~20 and was concentration-dependent. At higher
doses and concentrations, the partitioning into blood cells appear to be saturated and blood/plasma
ratio decreased to as low as ~2 to 3. The intravenous PK profile in blood but not in plasma (rats)
exhibits a plateau at earlier time points ( upto 2h post dose) after which it follows
monoexponential decline. The plasma concentrations shows biexponential decline with initial rapid
distribution phase (probably due to rapid distribution to blood cells).
A similar concentration dependent partitioning into blood cells was observed in an in vitro assay
using human blood.
We plan to use whole blood matrix (instead of plasma) for quantification of compound and subsequent
PK assessments further during development path.
I would highly appreciate if experts could help in getting answers to my questions as below.
1. Can anyone provide more understanding on concentration dependent blood cell partitioning and
its implications on further development of the compound?
2. Which matrix (blood vs plasma concentration) needs to be considered for risk assessment of
liabilities like DDI due to CYP inhibition/induction?
3. Are there any specific toxicity parameters (apart from those mentioned by Peter Hinderling in
Pharmacol Review) we need to monitor for this compound ?
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