Bioequivalence and Bioavailability Forum

Dear Vuvraj!

❝ I have got following parameters:

❝ Tmax, Cmax, AUC, Vz_Obs, Vz_Pred, Vss_Obs, Vss_Pred, CL_Obs, CL_Pred.

You can’t learn pharmacokinetics from a webforum. I would strongly suggest to read textbooks on PK, get some training in PK, or – as a starter – have a look at David Bourne's excellent ‘A First Course in Pharmacokinetics and Biopharmaceutics’. It doesn’t make sense to click through a piece of specialized software without knowledge of the basics behind. Sorry, there are no shortcuts.

Again, RTFM! For NCA formulas see WinNonlin’s User's Guide > WinNonlin Model Libraries > Noncompartmental analysis > Plasma or serum data.

There’s no consensus on terminology in PK. This may sound strange more than 50 years after publication of the first textbook.¹ That’s the reason many papers in the Journal of Pharmacokinetics and Pharmacodynamics still contain a section of abbreviations and definition of terms.

❝ [...] how to calculate Vc?

❝ Is Vc or Vz_obs same?

V_c is the Volume of the central compartment in a multi-compartment model used in textbooks e.g, Gibaldi/Perrier,² Wagner,³ and more recently Gabrielsson/Weiner.⁴ WinNonlin uses the term V₁ for the central and V_2-3 for the first and second [sic] peripheral compartment(s). Unless your drug shows more than one segment in a semilog plot and you perform PK-modeling, you will not obtain V_c. Therefore in NCA you only get parameters based on the apparent elimination phase.

Even if V_c is used, the numbering of transfer rate constants still uses 1 for the central compartment:^{[2, p.49]}

+-------------+  k12   +-------------+
|   Central   | ----→ | Peripheral  |
| Compartment | ←---- | Compartment |
+-------------+  k21   +-------------+
       |
       | k10
       ↓

Note: k₁₂, k₂₁, k₁₀ (not k_c2, k_2c, k_c0). The index 0 denotes ‘one-way-compartment’ of no defined volume. For extravasal administration the absorption rate constant is given as k₀₁ (or k_a), all elimination processes are denoted by k_i0 (e.g., k₁₀ from central or k₂₀ from the first peripheral). In a one-compartment model elimination sometimes is also denoted as k_el. All elimination processes may be composites of elimination of the parent drug and formation of metabolite(s). Unless you have metabolite data, you cannot distinguish between them. If multi-compartment models are concerned, there are many (!) different ones describing the data equally well (i.e., the same minimum SSQ, but different parameter values). Sampling from only the central compartment will give you no clue, which one is the “right” one. This problem is called model identifiability. You see, PK can be quite tricky. Therefore, if possible stick with NCA until you know what to do.

For PK formulas see WinNonlin’s User’s Guide > WinNonlin Model Libraries > Pharmacokinetic models >

• Model 2 (infusion, 1 compartment),
• Model 9 (infusion, 2 compartments),
• Model 19 (infusion, 3 compartments).

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References:
1. Dost FH. Der Blutspiegel: Kinetik der Konzentrationsabläufe in der Kreislaufflüssigkeit. Leipzig: Thieme-Verlag; 1953 (in German).
   
2. Gibaldi M, D Perrier D. Pharmacokinetics. New York: Marcel Dekker; 2^nd ed. 1982 (reprint: New York: informa healthcare; 2007).
   
3. Wagner JG. Pharmacokinetics for the Pharmaceutical Scientist. Lancaster: Technomic Publishing; 1993.
   
4. Gabrielsson J, Weiner D. Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications. Stockholm: Swedish Pharmaceutical Press; 4^th edition 2006.