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The following message was posted to: PharmPK
I have IV PK data at two doses and oral PK data at a single dose for
a compound for which I would like to determine bioavailability. The
compound was administered to CD-1 mice. I am not entirely sure I am
using the appropriate software model to evaluate my data (I used
WinNonLin noncompartmental analysis), but my AUCinf for the two IV
doses does not appear to be dose proportional.
20 mg/kg AUCinf = 300842 min*ng/ml
10 mg/kg AUCinf = 214368
The AUCinf for the oral dose (20 mg/kg) is 210684.
Other relevant parameters for each dose are
IV 20 mg/kg
Cmax = 4745 ng/ml
Cl = 1.48 ml/min
IV 10 mg/kg
Cmax = 6327 ng/ml
Cl = 1.02 ml/min
Oral 20 mg/kg
Cmax = 2698 ng/ml
Cl = 2.3 ml/min
Right away because my Cmax is lower for 20 mg/kg than for 10 mg/kg I
am suspecting a solubility issue (this compound is incredibly
hydrophobic.) It was formulated for both IV and oral doses as 5%
DMSO, 23% PEG400, 70% 0.1 M NaBicarbonate, and 2% Tween 80.
Are there other possibilities for these data? Also, how many more
doses should I evaluate before I have data that can be used to
determine bioavailability? Do I need to demonstrate dose proportional
PK for both IV and oral doses? Should I be analyzing the data
differently - i.e. Is noncompartmental analysis the best model to use
and/or should I be calculating bioavailability using something other
than the simple AUC oral/AUC IV X Dose IV/Dose oral assuming I ever
get to a place where AUC is proportional to dose.
Any general advice on this topic as well would be greatly
appreciated. I have read many of the posts on bioavailability, and I
understand the need for linear PK. I just don't know quite how to
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Data suggest that your cmpound exhibits Non-linear PK.
Since No data for 10 mg oral dose is available, currently it can be
presumed from IV data that the non linearity is not because of
Autoinduction of CYP because of thresold conc.or multicompartment PK
could be one of the reason.
get the data of 10 mg oral dose, compare the bioavialability.
As we know Bioavailability is mainly considered by AUC, less Cmax at
higher IV dose is a not surrogate for BA decision.
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