Bioequivalence and Bioavailability Forum

Hi mittyri,

❝ now try something with horrible enterohepatic cirulation

The masochistic part of my psyche is limited.*

However, the method is not a Swiss army-knife. I would never perform a pivotal replicate study without a pilot in order to see what’s going on.

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• OK, OK, my curiosity won.
  Highly lipophylic drug, ~50% excreted unchanged into the bile, documented enterohepatic recycling. No idea why this study was performed in a 2×2×2 crossover in two groups (ended in a deficiency about a ‘significant group-by-treatment interaction’…). Why not a 4-period full re­pli­cate in one group?
  115 eligible subjects, target metrics C_max, AUC_0–72. t_½ 10.6 h, recalculated residual AUC ~15% (2.2% – 86%!). CV_intra of AUC_0–∞ larger than the one of C_max.
  
  

  

  $$\small{\begin{array}{lrcccccr}
  \hline
  \;\;\;\;\;\;\;\text{PK metric} & \text{PE}\;\; & \text{90% CL}_\textrm{lower} & \text{90% CL}_\textrm{upper} & \text{width} & CV_\textrm{intra} & CV_\textrm{inter} & n\;\;\\\hline
  AUC_{0-\infty} & 93.35 & 85.38 & 102.07 & 16.68 & 42.54 & 45.11 & 74\\
  AUC_{0-\infty}\cdot k & 93.67 & 86.43 & 101.51 & 15.08 & 38.04 & 39.58 & 60\\
  C_\textrm{max} & 95.55 & 87.92 & 103.84 & 15.92 & 39.47 & 36.23 & 64\\
  C_\textrm{max}/AUC_{0-\infty} & 102.35 & 96.78 & 108.23 & 11.45 & 25.98 & 29.61 & 30\\
  C_\textrm{max}/AUC_{0-\infty}\cdot k & 102.69 & 91.81 & 114.86 & 23.05 & 54.74 & 65.53 & 114\\\hline
  \end{array}}$$ \(\small{n}\): Sample size for 2×2×2 crossover, T/R-ratio 0.95, ≥80% power.
  Lots of limitations: Poor estimation of \(\small{\lambda_\textrm{z}}\) (n = 3: 218, n = 4: 12), likely not the terminal phase (reported t_½ 20 – 36 h), in 35.7% of cases extrapolated AUC >20%.
  Required sample sizes: \(\small{AUC_{0-\infty}\cdot k}\) vs \(\small{AUC_{0-\infty}}\) –19%, \(\small{C_\textrm{max}/AUC_{0-\infty}}\) vs \(\small{C_\textrm{max}}\) –53%.
  \(\small{C_\textrm{max}/AUC_{0-\infty}\cdot k}\) is awful. Why?