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Dear all,
I have recently encountered some difficulty trying to estimate the
drug exposure following multiple SC dosing and would like to get some
input from you. We have this drug candidate A to be tested in a mouse
tumor model. The treatment lasted for about 30 days. Four different
dosing schemes were tested: SC bid, SC qd, SC qod and SC biw. Since
we could only take limited serum samples from those mice, a total of
6 samples were taken during the 30 days. They are either peak samples
at the estimated Tmax for each dosing interval, or trough samples at
the time right before the next dose. We do have a full PK on this
molecule in normal CD-1 mice. To evaluate the impact on PK by the
tumor implant as well as chronic dosing, I did some PK simulations
based on the normal mouse PK parameters. For the least frequent
dosing scheme, i.e. SC twice a week, the observed serum
concentrations matched well with the simulations. However, for the
other three dosing groups, the observed concentrations turned out to
be lower than the projected values, especially for the trough
concentrations, they could sometimes be 2 logs lower than the
simulations. In a previous experiment, the drug candidate was dosed
at the same dosing frequency but different doses, which made it easy
for me to simply average the Cmax and Cmin for each individual and
use the Cavg on the x-axis to compare their conc-response curves
(tumor size at the end of the study was used as the response
variable). However, in this current experiment, since the drug was
dosed at different intervals, a simple Cavg (=Cmax/2+Cmin/2) is going
to mask the real difference in exposure AUC's. The only thing that I
could think of right now is to manually adjust the PK parameters in
my simulation model and try to match the curve fits with the observed
peaks and troughs for each individual animal and use the simulated
AUC or Css to do my conc-response analyses---which is very much
arbitrary with only two data points in one dosing interval and three
parameters (V/F, K01 and K10) to change. I would really appreciate
any input from you to solve this problem!!
Thanks!
Yinuo Pang
Senior Scientist
Department of Experimental Pathology and Pharmacology
Schering-Plough Biopharma
Palo Alto, CA
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