Bioequivalence and Bioavailability Forum

Dear D. Labes!

❝ From the same times (but a tick later) originates the TOPFIT solution, a program running under MS-DOS:

Oh, TopFit (like billards it required a combination of imagination, skill, patience, and devotion). I wouldn’t call it a dinosaur – at sweet seventeen has not reached adolescence yet.

• Heinzel G, Woloszczak R, Thomann P. TopFit Version 2.0: Pharmacokinetic and Pharmacodynamic Data Analysis System for the PC. Stuttgart, Jena, New York: Gustav Fischer; 1993.
  
• Tanswell P, Koup J. TopFit: a PC-based pharmacokinetic / pharma­co­dynamic data analysis program. Int J Clin Pharmacol Ther Toxicol. 1993;31(10):514–20.

What I really liked, was the ingenious method of running any model without initial estimates – even the most ambitious user defined ones. At that time PCNONLIN drove my crazy because I couldn’t find suitable ones in many cases. When I switched to the first version of WinNonlin (mainly for the graphical capabilities) I still (mis)used TopFit to get initial estimates for tricky models.

❝ 1. Calculate regression line of the terminal part of excretion

❝   rates to obtain lambda_Z (like Far side solution)

❝ 2. calculate excretion rate at t_last from that regression line

❝ 3. Ae(inf) := Ae(t_last) + excretion_rate((t_last)/lambda_Z

Are you sure?


Step 1 gives lambda_Z 0.1545, t½ 4.49
Step 2 gives 69.50 (measured 62.40) ^{* see my edit at the end}
Step 3 gives 8642.7+69.5/0.1545=9092.68 but I can't find it in TopFit: ============================================================================
TopFit V 2.0                                                     Page 2 of 3
                     *** NON-COMPARTMENTAL ANALYSIS ***
File : WNLURINE                                              9.04.2010 16:56
============================================================================
Formulation no                                                             1
Type of formulation                                      Absorption (Tablet)
Name of formulation                                            WNL Urine.pwo
----------------------------------------------------------------------------
                            *** DOSING TABLE ***
             No           Time           Dose       Duration          Entry
                        [hour][mg/individual]                   compartment
----------------------------------------------------------------------------
              1        0.00000       10.00000        0.00000              0
----------------------------------------------------------------------------
Data set no                                                                1
Sample matrix                                                          Urine
----------------------------------------------------------------------------
             No           Time          Value              R
                        [hour]           [mg] ----------------------------------------------------------------------------
              1        0.00000        0.00000
              2        2.00000      420.00000
              3        4.00000     1377.00000
              4        6.00000     4372.20000
              5       10.00000     6198.00000
              6       18.00000     8268.30000
              7       24.00000     8642.70000
----------------------------------------------------------------------------
             No           Time      Excretion              R
                                        Rates
                        [hour]      [mg/hour]
----------------------------------------------------------------------------
              1        1.00000      210.00000
              2        3.00000      478.50000
              3        5.00000     1497.60000
              4        8.00000      456.45000              *
              5       14.00000      258.78750              *
              6       21.00000       62.40000              *
----------------------------------------------------------------------------
* in column R marks values which are used for regression

============================================================================
TopFit V 2.0                                                     Page 3 of 3
                     *** NON-COMPARTMENTAL ANALYSIS ***
File : WNLURINE                                              9.04.2010 16:56
============================================================================
             No           Time         (Ui-U)              R
                        [hour]           [mg] ----------------------------------------------------------------------------
              1        0.00000     8642.70000
              2        2.00000     8222.70000
              3        4.00000     7265.70000
              4        6.00000     4270.50000              *
              5       10.00000     2444.70000              *
              6       18.00000      374.40000              *
----------------------------------------------------------------------------
* in column R marks values which are used for regression

                *** MRT mean residence time (excretion) ***
                        Lambda             t½            MRT
                      [1/hour]         [hour]         [hour] ----------------------------------------------------------------------------
excretion rates        0.15445        4.48778        8.74997
           Ui-U        0.20737        3.34248        8.77977
Ui extrapolated        0.14621        4.74068        8.74836
----------------------------------------------------------------------------
Total amount excreted                                   [mg]      8925.8

There’s another fit – corresponding to the table above:

According to the documentation 2-58:

The amount excreted at t_last is assumed to be the Ae_inf-value.

My emphasis. Nice assumption. Why try to extrapolate, if we already ‘know’ the value - because we have sampled until complete excretion). That's corresponding to Gabriels­son’s/Weiner’s ARE-method (Amount Remaining to be Recovered).
From this fit we get lambda_Z 0.2074, t½ 3.34; now what?
Never try to ‘understand’ software you haven’t written yourself.

---

Edit: Now I got it. t_last = 24 - not the last midpoint time (21). You stated this in your step 2 (Lesen bildet). Therefore the estimated last rate 43.27, 8642.7+43.27/0.1545=8925.82, matching TopFit.