Bioequivalence and Bioavailability Forum

Dear Imran!

❝ The step I followed calculation of PK Parameters is as: PK/PD/NCA Analysis Wizard , noncompartment modeling, select model 200, data variables, dosage regimen and selecting steady state followed by modeling, generation of PK output.

Yes fine, but the order in Dosage Regimen is:
[x] Steady state
Dose
Time of Last Dose
Tau

❝ The XL file I have attached, the data processed is excluding trough sample (day1, 5, 6 and 7), [...]

Sure, you are interested in the profile (WinNonlin simply ignores the saturation phase, which is fine).

❝ should I process trough data and profiling data separately.

In versions 5.1+ you may run a linear regression of e.g., the last three trough values to check whether you have reached steady state (95% CI of the slope should include zero).
Model 502 (Linear) of example's data below give:
Last 4 troughs (24 h - 96 h): slope 0.063, CI -0.049, +0.176
Last 3 troughs (48 h - 96 h): slope 0.019, CI -0.120, +0.158
...so you may assume steady state conditions.

❝ As u wrote in ur mail that in WinNonlin %PTF to be calculate manually, but here in my case I calculated all of the primary and secondary parameters [...]

Oh, you are right!

❝ I have troubleshooting how the data to be presented in the WinNonline, I tried in all the possible way, but I am not sure about the output.

Why don't you keep it simple and check the results manually?
OK, I've done that for you...

D=100, V/F=1, k01=0.6931, k10=0.06931, tau=24h for five days gives (rounded to 1 decimal place):
time conc
 0    0.0
 24  21.1
 48  25.0
 72  25.8
 96  25.9
 98  91.5
 99  97.4
100  96.9
102  88.7
104  78.3
106  68.4
109  55.7
112  45.2
116  34.3
120  26.0

Now let's have a look at the output (Non-Transposed Final Parameters Tab), and a 'manual' calculation
          WinNonlin5.2  'manual'
AUClast       1425.4     1425.4
Cmax            97.4      97.4
Cmin            25.9      25.9
Tmin            96        96
Cav             59.4      59.4
%Fluctuation   120.3873  120.3873
AUCtau        1425.4    1425.4
AUCall        1425.4    1425.4

Fine.
Please note, that AUClast = AUCtau = AUCall.
Generally nobody is interested in the sampling beyond the last administration + tau, but in your case obviously this was the case (+72 hours).

If we add two more samples (144 h, 168 h), WinNonlin's output might get a little bit confusing for a novice, since:
time conc
  0   0.0
...   ...
120  26.0
144   4.9
168   0.9

          WinNonlin5.2  'manual'
AUClast       1865.8    1865.8
Cmax            97.4      97.4
Cmin            25.9      25.9
Tmin            96        96
Cav             59.4      59.4
%Fluctuation   120.3873  120.3873
AUCtau        1425.4    1425.4
AUCall        1865.8    1865.8

WinNonlin is 'clever' enough to keep AUCtau (and therefore Cav, and %Fluctuation correct within tau), but please note AUClast # AUCtau and AUCall!

If we sample for another 48 hours until we get a BLQ:
time conc
  0   0.0
...   ...
168   0.9
192   0.2
216   BLQ

          WinNonlin5.2  'manual'
AUClast       1879.0    1879.0
...              ...       ..
AUCtau        1425.4    1425.4
AUCall        1881.4    1881.4

Now finally we ran into AUClast # AUCtau # AUCall!
AUCall adds a triangle from the Tlast to the next sampling time point, assuming C=0. If you know of any serious reference using AUCall, please tell me. It's Pharsight's invention and IMHO useless - I removed it from my templates...
It's also funny that Pharsight's business rival Thermo_Scientific added this 'metric' to Kinetica as well.

In short:

• Sample only until last administration + tau,
  
• WinNonlin gives the correct result for %Fluctuation,
  
• Don't get confused; it's only AUCtau you are interested in.

❝ Primary Efficacy Parameters: Cmin, Cmax, AUC0 - 

❝ Secondary Efficacy Parameters: Tmax, % Fluctuation

In BA/BE we should not talk about Efficacy...