Bioequivalence and Bioavailability Forum

Dear neoc!

❝ I want to do noncompartmental PK analysis of a drug (drug "A").

❝ The goal is to see whether or not a second drug (drug "B") shows effect on

❝ PK parameters of drug A.

❝ The studydrug was administered twice as an IV bolus dose of 1 mg injected

❝ over 1-2 minutes, at t=0 min and t=40 min. The half life was estimated at

❝ 200 min. On two separate occasions subjects took either only drug A or a

❝ combination of drug A and B

❝

❝ The question: What kind of modelsettings/dosing regimen is best to choose?

❝

❝ The drug is dosed twice, but no steady state concentration is reached.

Were there any particular reasons for this design? 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 http://www.fda.gov/cder/guidance/2635fnl.pdf 1999, http://www.fda.gov/cder/guidance/6695dft.pdf 2006, CAN-HPB).

Actually right now you are assessing just the beginning of the saturation phase - which my vary between subjects...

❝ - Should I use an NCA IV bolus model with single dosing (e.g. 2 mg total

❝ dose) with time of dosing at t=0.

❝ - Should I use the steady state option in the dosing regimen window, using

❝ something as: Dose: 1, Tau=40 min, Last dose=0. In this way I can define

❝ the multiple dosing, however, no steady state is reached, so I feel the

❝ first option is better.

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); in the Parameter names tab of the Model Options for NCA Model 201 change all parameters which will use the dose in calculations (Cmax_D, C0, AUCINF_D_obs, AUCINF_D_pred, Vz_pred, Cl_pred, Vss_obs, Vss_pred) in column 'Include in Workbook' from 'Yes' to 'No'. These parameters depend on a correct dose definition - which is not true. Attention: these settings apply only to the workbook, but are still given in the NCA Text file - don't use them!

I'm afraid you have to struggle with the evaluation of a flawed design. The 'correct' evaluation would be assessment of the first profile only - but probably you have just a few data points there...

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Edit: Links corrected for FDA’s new site. [Helmut]