Bioequivalence and Bioavailability Forum

Servus Franz!

❝ Considering the PK of Azithromycin, "the less the better" could be considered, because there are (at least?) 3 elimination phases […]. As terminal elimination needs to be calculated and the adj r² method from previous study took mostly 3 to 5 points, but sometimes also 12 (!), should the timepoints be limited (to 4 to 3), to reflect PK?

Multiphasic PK can be problematic, especially if volumes of distribution are variable. I once had to deal with a drug (3 phases) where the terminal half life was ~3 days and the volume of distribution of the deep compartment was very large. Was this phase important? No. Running a PopPK model it turned out that this compartment accounted for <1% of the AUC. In my case the V₂ showed little variability, but if we have large variability the predominant half life in some subjects might be the second phase and the third in others… See also Boxenbaum & Battle (1995).*

❝ What if one concentration looks to be an analytical mistake(?), that confounds t_1/2 in such a way that the slope increases...?

Since according to the EMA’s bioanalytical GL a blind plausibility review of data leading to confirmation/rejection (aka “pharmacokinetic repeat”) is not acceptable any more – bad luck. If other countries are concerned: Have an SOP in place, repeat the analysis, and cross fingers. Other options (?):

• Exclude the suspect value from the estimation of λ_z. Keep it in the calculation of AUC_t and base the calculation of AUC_∞ not on C_t, but on its estimate (in Phoenix/WinNonlin’s terminology: AUCinfpred instead of AUCinfobs).
  
• Exclude to subject from the comparison of AUC, but keep him/her for the comparison of C_max. Since the latter is more variable and the study should be powered to show BE for the most variable metric it should not hurt too much.
  
• If you expect problems beforehand – and have an IR formulation – go with AUC₇₂ instead. No more hassle with extrapolations.

Of course everything should be covered by SOPs and – preferably – described in the protocol as well.

❝ Where to put the cut-off for adj r²?

Nowhere. Forget it. Doesn’t make any sense, IMHO. For a bad example see this thread. I would be happy to see a publication justifying an algorithm which would allow automatic selection of the terminal phase in multicompartment PK. If anybody knows a single one, please let me know. See also Ref.#2 at the end of this thread.

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• Boxenbaum H, Battle M. Effective Half-Life in Clinical Pharmacology. J Clin Pharmacol. 1995; 35(8): 763–6. doi:10.1002/j.1552-4604.1995.tb04117.x.