Bioequivalence and Bioavailability Forum

Thanks for your reply!!

❝ Were there any particular reasons for this design?

The only reason for this strange dosing regimen I could find was safety: in case too many side effects occurred in the first dosing, the second dosing would not be administered (it was an ACh inhibitor). I have still only little knowledge on trial design buy I think an IV infusion over 30-60 minutes would have been better. If side effects would become to strong, drug infusion could always be terminated.

❝ To perform a PK interaction study (which is by design and it's

❝ evaluation basically a BE study), we should look either at single

❝ dose or steady state, although according to the guidelines

❝ a steady state study is either mandatory (EU-EMEA) or should

❝ be considered (US-FDA 1999, 2006)

Actually the primary goal was to asses the efficacy of additional administration of drug B on the already proven effect of drug A. For sake of simplicity I left this out. I think the NCA PK analysis can be seen as post-hoc, and therefore not explicitly mandatory.

❝ Actually in WinNonlin you have only one option, namely the wrong one.

❝ If you go with the SS option (which would allow you to input correct doses

❝ and tau), you will end up with AUC_tau (in WinNonlin's output

❝ given as AUClast = AUC from t=tau to t=last) only. Even AUCinf will be

❝ wrong, because the first profile will be simply ignored in the

❝ calculations.

❝ In order to calculate the AUC over both profiles, you will have to uncheck

❝ the [x] Steady state option in the Dose regimen tab of NCA Model 201. You

❝ may input any value for dose (acting just as a dummy);

Currently I choose to use the NCA 201 model without SS. For dosing I entered the total dose of 2 mg (2x1mg) with dosing at t=0.
The main parameters I'll have to calculate are Thalf, Cmax and Clearance. Clearance is calculated from AUCinf by Cl=D/AUCinf, and Thalf is based on the curve fitting part (Lambda_Z). When choosing for NCA 201 *with* SS, WinNonLin gives me the same values for AUCinf (seems logical), and therefore actually there is no change in the final parameters I need. (If my method is correct off course!).
However, someone else (which I cannot reach right now) wants to use my WinNonLin modeling data for doing some compartmental analysis in NONMEM. Does it matter which method (SS or no SS) I use? E.g. I don't know if the specific SS parameters such as Clss, AUC_Tau etc. would be needed for a compartmental analysis. I would guess some estimates of Lambda_Z and AUC_inf might come in handy for the NONMEM analysis, but I doubt parameters such as Clss will, because no actual SS is reached yet probably.

I would appreciate it if you (HS) or someone else would be able to clarify this last hesitation!

Thank you!