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recently i came across amprenavir dose dependent data. the following is
1. the increase in AUC with increasing dose is more than dose
2. the increase in Cmax with increase in dose is less that dose
now # 1 can be explained on the basis of saturable metabolism and
efflux. but how does one justify #2 ?
what could be the reason for an less than dose proportional increase?
i understand that Cmax/Tmax are functions of Ka and Kel but there is no
known absorptive transporter involved with amprenavir and hence that can
be ruled out. is solubility a issue? or incomplete absorption?
any inputs will be appreciated.
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Without knowledge of specific pharmacokinetic data regarding
amprenavir, the more than dose proportional "nonlinear" increase in
AUC could be explained by saturable enzyme kinetics as in the case
of phenytoin. The increase in Cmax which is less than dose proportional
could be explained by a decrease in Ka.
The relevant first order absorption kinetics could be simplified
in the "linear" case as follows:
Tmax= [1/(Ka-Ke)]*Ln(Ka/Ke) equation 1
Cmax= (FXo/Vd)e-KeTmax equation 2
Equation 1 predicts an increase in Tmax with a relative decrease
in Ka. The increase in Tmax results in a decrease in Cmax according
to equation 2. A decrease in Ke resulting from "nonlinear" saturable
kinetics would modify this process, tending to increase Cmax out of
proportion to dose according to equation 2. However, an increase in
Cmax which is less than proportional to dose would suggest that there
has been a greater decrease in Ka relative to Ke, since nonlinear
kinetics would tend to have the opposite effect
Coincidently, phenytion exhibits similar pharmacokinetics with
large oral doses, where the Ka tends to decrease as phenytoin tends
to complex in the GI tract, and the Ke tends to decrease as the
enzyme system becomes more saturated.
Mike Leibold, PharmD, RPh
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