Bioequivalence and Bioavailability Forum

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log-in |  Register |  Search

Back to the forum  Query: 2017-12-13 08:31 CET (UTC+1h)
 
Mahesh M
Regular

India,
2017-07-06 06:45

Posting: # 17512
Views: 1,343
 

 multiple dose steady state BE and emesis criteria [Regulatives / Guidelines]

Dear All,

Please suggest, for multiple dose steady state BE study(day 1 -5), If any subject vomit between the day 1-2 and 1-4, what will be the withdrawal criteria? If steady state achive in three days and emesis occur on day one or day two should we continue the subjects.

Regards
M
Mahesh M
Regular

India,
2017-07-14 12:31

@ Mahesh M
Posting: # 17547
Views: 991
 

 multiple dose steady state BE and emesis criteria

Dear All,

Any thoughts on that. Please share.

Regards
M
jag009
Hero

NJ,
2017-07-20 05:15

@ Mahesh M
Posting: # 17565
Views: 891
 

 multiple dose steady state BE and emesis criteria

Haven't ran SS BE studies for a long time... If you have 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).

John
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-22 15:12

@ jag009
Posting: # 17593
Views: 837
 

 regression of pre-dose concentrations

Hi John,

» […] 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

Consequently the EMA requires only reporting pre-dose concentrations.
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

Better (R2 0.5197) but you would still exclude profiles.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
mittyri
Senior

Russia,
2017-07-23 11:52

@ Helmut
Posting: # 17595
Views: 797
 

 Which method for SS achievement?

Hi Helmut,

» » […] 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.

I'm confused...
Then which method would you recommend instead? :confused:

Kind regards,
Mittyri
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-22 15:33

@ Mahesh M
Posting: # 17594
Views: 829
 

 IR and MR: pre-specified!

Hi Mahesh,

» If any subject vomit between the day 1-2 and 1-4, what will be the withdrawal criteria? If steady state achive in three days and emesis occur on day one or day two should we continue the subjects.

Depends on the formulation. I apply the same rules like in a SD study but irrespective whether emesis occurs in the saturation phase or on a profile day.
  • IR:  ≤2× median tmax of the reference.
  • MR: anytime within the labeled dosing interval.
FDA:

We recommend that data from subjects who experience emesis during the course of a BE study for immediate release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. For modified release products, we recommend deleting data from the analysis if a subject vomits during a period of time less than or equal to the dosing interval stated in the labeling of the product.

EMA:

Examples of reasons to exclude the results from a subject in a particular period are events such as vomiting […] which could render the plasma concentration-time profile unreliable.
The permitted reasons for exclusion must be pre-specified in the protocol. If one of these events occurs it should be noted in the CRF as the study is being conducted. Exclusion of subjects based on these pre-spe­ci­fied criteria should be clearly described and listed in the study report.


[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum | Admin contact
17,556 Posts in 3,758 Threads, 1,091 registered users;
30 users online (0 registered, 30 guests).

The purpose of models is not to fit the data,
but to sharpen the questions.    Samuel Karlin

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
XHTML/CSS RSS Feed