Predominant half life; exclusions [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2012-10-08 15:45 (4188 d 21:44 ago) – Posting: # 9334
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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 t1/2 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 (?):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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