PharmPK Discussion - Exposure using Cmax and Cmin following multiple SC dosing

• On 3 Apr 2007 at 14:52:30, "Pang, Yinuo" (Yinuo.Pang.-at-.spcorp.com) sent the message
  

  
  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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