regression of pre-dose concentrations [Regulatives / Guidelines]
Hi John,
Been there, done that. Nowadays I don’t recommend it any more. Testing the slope for ≠ 0 (or assessing whether its CI does not contain 0) will lead to exclusion of ~5% of profiles (since we falsely conclude that we are not in steady state).
Small simulation: t½,el 12 h, t½,abs 3 h, τ 24 h, 5×t½,el to reach “steady state”, profile on day 6, analytical variability 2.5–25% (excellent to lousy), concentrations lognormal, 50,000 profiles, regression of pre-dose concentrations (t 72, 96, 120 h), test for a significant p of the slope.
IIRC, in Taiwan one must sample beyond τ in order to estimate t½,el. Duno whether subjects have to be excluded if “steady state” was not reached as planned.
There is a correlation (R2 0.9593) of p-values and the variability of the analytical method. Makes sense. If we design the study with 5×t½,el, concentrations are still increasing (positive slopes). Good analytical methods will detect that. With not so good methods it will be hidden in random noise.
Same game with a longer saturation phase (7×t½,el):
❝ […] 3 consecutive day samples to assess steady state then it should be fine as long as you can demonstrate that steady state is achieved (regression analysis).
Been there, done that. Nowadays I don’t recommend it any more. Testing the slope for ≠ 0 (or assessing whether its CI does not contain 0) will lead to exclusion of ~5% of profiles (since we falsely conclude that we are not in steady state).
Small simulation: t½,el 12 h, t½,abs 3 h, τ 24 h, 5×t½,el to reach “steady state”, profile on day 6, analytical variability 2.5–25% (excellent to lousy), concentrations lognormal, 50,000 profiles, regression of pre-dose concentrations (t 72, 96, 120 h), test for a significant p of the slope.
CV (%) p <0.05 (%)
───────────────────
2.5 5.10
5 5.03
7.5 5.05
10 4.98
12.5 4.93
15 4.87
17.5 4.89
20 4.79
25 4.75
IIRC, in Taiwan one must sample beyond τ in order to estimate t½,el. Duno whether subjects have to be excluded if “steady state” was not reached as planned.
There is a correlation (R2 0.9593) of p-values and the variability of the analytical method. Makes sense. If we design the study with 5×t½,el, concentrations are still increasing (positive slopes). Good analytical methods will detect that. With not so good methods it will be hidden in random noise.
Same game with a longer saturation phase (7×t½,el):
CV (%) p <0.05 (%)
───────────────────
2.5 4.83
5 4.87
7.5 4.83
10 4.83
12.5 4.90
15 4.85
17.5 4.80
20 4.73
25 4.71
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- multiple dose steady state BE and emesis criteria Mahesh M 2017-07-06 06:45 [Regulatives / Guidelines]
- multiple dose steady state BE and emesis criteria Mahesh M 2017-07-14 12:31
- multiple dose steady state BE and emesis criteria jag009 2017-07-20 05:15
- regression of pre-dose concentrationsHelmut 2017-07-22 15:12
- Which method for SS achievement? mittyri 2017-07-23 11:52
- regression of pre-dose concentrationsHelmut 2017-07-22 15:12
- multiple dose steady state BE and emesis criteria jag009 2017-07-20 05:15
- IR and MR: pre-specified! Helmut 2017-07-22 15:33
- multiple dose steady state BE and emesis criteria Mahesh M 2017-07-14 12:31