NCA agrees with PK-modeling [Software]
❝ I am still curious about calculation of CL and MRT. As CL=Dose/AUC and MRT=(AUMC/AUC) - (Duration of Infusion/2). These parameters are dependent on AUC & AUMC.
Correct so far.
❝ And the problem with AUC & AUMC I see is that baseline being 10, the calculated AUC is sum of exposure due to second dose + exposure due to the baseline concentration of drug already present, which can contribute to as high as 10% of total AUC (200 at Cmax, 10 at 0h).
Maybe you were confused by the fact that you measured 10 both at the start and the end of the second infusion (sorry for drawing the red line in my first post). Due to the fact that you are close to the LLOQ that might be just a coincidence (random noise). Since this was not an endogenous compound, there is no „baseline”. You have residual concentrations of the first infusion which gradually are eliminated. In my simulation the residual concentration is 9.55 at four hours and just 0.45 at eight hours (note that 9.55+0.45=10). Below the model:
❝ In this situation do you think these parameters (CL and MRT) will still be good representative of Plasma PK for this drug?
NCA is fine as long as
- you assume linear PK (superposition principle holds),
- you assume that you are sufficiently close to steady state, and
- you use my setup.
❝ or there is way to analyze it better?
There is no free lunch. Of course modeling might be an alternative. Depends on your experience and the purpose of the study. Let’s compare NCA (lin-up log-down trapezoidal) with PK models (one compartment, parameterized in CL & V, duration of infusions five minutes):
NCA 1 2 3 4
VSS mL 508.98 507.12 507.13 507.13 484.40
CL ml/h 388.88 387.89 387.87 387.88 370.49
AUC h×µg/mL 257.15 257.81 257.82 257.81 269.91
AUMC h²×µg/mL 294.97 337.05 337.08 337.07 352.90
MRT h 1.3088 1.3074 1.3075 1.3074 1.3075
- The data of the first infusion (which you don’t have).
- The data of the second infusion; both doses given in the setup.
- The data of both infusions.
- The data of the second infusion but only the second dose given in the setup.
t½ was 0.90624 h. That means we reached 100(1–½4/0.90624)=95.31% of steady state at the start of the second infusion. Should be sufficient. Quick & dirty: 100×C4/C8=95.5%.
Since we didn’t give the first dose (classical user error) in model 4, Phoenix does its best to fit the data but the results are wrong. Rubbish in, rubbish out.
BTW, it is one of the mysteries of Phoenix/WinNonlin why the NCA’s MRT is correct though the AUMC isn’t. My pocket calculator gives 294.97/257.15=1.1471.

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Helmut Schütz
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Science Quotes
Complete thread:
- WinNonlin: NCA of multiple dosing plasma PK profile bobmarlo 2017-01-15 17:22 [Software]
- WinNonlin: steady state setup Helmut 2017-01-16 13:15
- WinNonlin: steady state setup BE-proff 2017-01-17 07:54
- Accumulation Helmut 2017-01-18 02:22
- WinNonlin: steady state setup bobmarlo 2017-01-17 20:36
- NCA agrees with PK-modelingHelmut 2017-01-18 01:41
- NCA agrees with PK-modeling bobmarlo 2017-01-18 05:06
- Winnonlin AUMC_TAU and others mittyri 2017-01-18 18:00
- NCA agrees with PK-modelingHelmut 2017-01-18 01:41
- WinNonlin: steady state setup BE-proff 2017-01-17 07:54
- WinNonlin: NCA of multiple dosing plasma PK profile mittyri 2017-01-16 17:29
- WinNonlin: steady state setup Helmut 2017-01-16 13:15