## large deviations from schedule [Regulatives / Guidelines]

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

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

» […] 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):

- Specify a maximum acceptable deviation and – if exceeded – compare AUCs up to the last common time point* (here 48 hrs).

- 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.

*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*J Clin Pharm. 2016; 56(7): 794–800. doi:10.1002/jcph.663. free resource._{last}(Common).

—

Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮

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*Dif-tor heh smusma*🖖_{}Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮

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### Complete thread:

- ambulatory samples in bioequivalence studies yoyo87 2020-11-22 10:06 [Regulatives / Guidelines]
- large deviations from scheduleHelmut 2020-11-23 12:18