Bioequivalence and Bioavailability Forum

Hi yoyo87,

» […] accepted deviation in time in ambulatory samples (24, 36, 48 and 72 hr) in bioequivalence studies?? example 6 hours deviation is accepted or not??

See also this recent thread. Well, six hours are extreme. I would even collect and analyze a 78 hr sample. Say, it was after the test-treatment and the reference was fine. If you don’t, you end up in your AUC_0–tlast comparison with AUC_0–48/AUC_0–72, which is an apples-and-oranges comparison (negatively biased). If you do, you end up with AUC_0–78/AUC_0–72, which is positively biased.

Two options (have to be stated in the protocol):

1. Specify a maximum acceptable deviation and – if exceeded – compare AUCs up to the last common time point* (here 48 hrs).
   
2. If this an IR formulation, specify pAUC_0–72 instead of AUC_0–tlast as the PK metric for extent of absorption. Work with an imputed (estimated) concentration:
   \(C_0=\exp\left(\frac{\log_{e}C_1\cdot(t_2-t_0)+\log_{e}C_2\cdot(t_0-t_1)\;}{t_2-t_1} \right)\), where the indices \(\small{1,\,2}\) denote the times and concentrations before and after the estimate denoted by the index \(\small{0}\).
   Say, you have \(\small{t_1=48,\:C_1=16}\) and \(\small{t_2=78,\:C_2=5.0897}\).
   At \(\small{t_0=72}\) you will estimate \(\small{C_0\approx\exp\left(\frac{2.77259\times6+1.62722\times24}{30}\right)\approx6.400}\):
   
   
   
   See also the second example in this post.

NB, I recommend to always use the linear-up/logarithmic-down trapezoidal rule for the calculation of AUC.

---

• Fisher D, Kramer W, Burmeister Getz E. Evaluation of a Scenario in Which Estimates of Bioequivalence Are Biased and a Proposed Solution: t_last (Common). J Clin Pharm. 2016; 56(7): 794–800. doi:10.1002/jcph.663. free resource.