Bioequivalence and Bioavailability Forum

Hi MGR,

THX for providing the data! If others are interested you may download them (in CSV-format).

❝ I have done the pharmacokinetic analysis using Phoenix WinNonlin 8.3…

❝ Could anybody help me how to calculate/formula/logic of Kel Value calculations as per ANVISA Regulatory?

No logic, only bad practices.

First of all, from subjects where concentrations are relatively high it is clear that the drug follows a two-com­part­ment model. In subjects with low concentrations only the distribution phase is visible, explaining also the reported half lives ranging from 0.57 to 9.55 hours.
The default automatic algorithm in Phoe­nix WinNonlin (and most other software I know) is starting with the last three concentrations and maximizing \(\small{R_\textrm{adj}^2}\) until the improvement by adding data is ≤0.0001. So far, so good.

• It works for two-compartment models reasonably well in most cases:
  
  
  
  
• However, it might fail in others:
  
  
  
  If the the distribution- and elimination-phases are not well separated, the algo is ‘greedy’, i.e., reaches too far. Then the estimated elimination is contaminated by the distribution and looks faster than it really is.

It was kind of a scavenger hunt to unveil what the ANVISA did. By trial-and-error I was successful at the end. Don’t know which software was used but for many years t_max|C_max is not included by the algo because absorption is not complete. Another example:

• Automatic:
  
  
  
  Fine with me. Maybe I would have used only the last three values.
  
  
• ANVISA:
  
  
  
  Why the heck?

Since the automatic algo might fail (sometimes with two-compartment models, regularly with drugs showing enterohepatic recycling, controlled release products with flat profiles, multiphasic release products), visual inspection of the fits is mandatory.

   The selection of the most suitable time interval cannot be left to a programmed algorithm based on mathematical criteria, but necessitates scientific judgment by both the clinical pharmacokineticist and the person who determined the concentrations and knows about their reliability.¹
   It should be emphasised that the TTT method has been introduced in this paper to provide a reasonable tool to support visual curve inspection for reliably identifying the mono-exponential terminal phase. Moreover, the TTT method should not be utilised without visual inspection of the respective concentra­tion-time course. Thus, before using this new approach the monophasic shape post the peak of the curve has to be checked visually by means of a semilogarithmic diagram.²

But what do we see in ANVISA’s examples? In many cases t_max|C_max was included. Outdated software?³ In some cases a quite reasonable automatic fit was changed to the worse. Very bad: The fits were corrected about three times as often for R than for T. If we would do that, an assessor might suspect cherry-picking (intentionally changing the T/R-ratio of AUC_0–∞).

My procedure (of course, outlined in the protocol):

• Perform NCA in a blinded manner (in Phoenix WinNonlin sort by period and subject). Use an automatic algo.
  
• Inspect all fits and correct the start/end-times if deemed necessary in a consistent manner.
  
• In newer versions of Phoenix WinNonlin lock the results.
  
• Join the randomization (i.e., unblind the data) and continue as usual.

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1. Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development: Methods and Appli­cations. New York: Wiley; 2007. p. 20-3.
   
2. Scheerans C, Derendorf H, Kloft C. Proposal for a Standardised Identification of the Mono-Exponential Terminal Phase for Orally Administered Drugs. Biopharm Drug Dispos. 2008; 29(3): 145–57. doi:10.1002/bdd.596.
   
3. Including t_max|C_max was implemented in ‘classical’ WinNonlin till v5.3 of 2009. The ANVISA’s manual is of 2002. Maybe that’s the reason.