mittyri
★★  

Russia,
2023-02-09 15:40
(531 d 10:44 ago)

Posting: # 23450
Views: 2,412
 

 Deconvolution sample size and design issues [Power / Sample Size]

Dear all!

I am puzzled with EMA MR Guide:

5.1.1. It should be demonstrated that the modified release formulation has the claimed release characteristics. It is encouraged to employ deconvolution of the concentration-time data for the modified release formulation against an appropriate immediate release formulation (see Appen­dix II for more detail) in order to obtain the cumulative absorption (or in vivo release) versus time profile for the modified release formulation.

I looked into Appendix II, it is named as "in vivo skin adhesion", nothing more. Is there another Appendix I missed?

1. Is it possible to evaluate the number of subjects used for the following cumulative absorption estimate?
2. Is it possible to get exp1/A1/exp2/A2 terms from non-IV data (say IR)?
3. Are there any examples of designs to be used for Deconvolution? As far as I can see, 3 periods are necessary, IV, IR, MR
4. I see many papers explaining deconvolution in range of IVIVC, are there any examples of EPARs you know where deconvolution is used clearly 'to obtain the cumulative absorption (or in vivo release) versus time profile for the modified release formulation'

Kind regards,
Mittyri
dshah
★★  

India/United Kingdom,
2023-02-09 17:20
(531 d 09:04 ago)

@ mittyri
Posting: # 23451
Views: 1,918
 

 Deconvolution sample size and design issues

Dear Mittyri!

Kindly see Appendix III. It is typo error.
For Point 1: I guess, it depends on variability. Kindly see point 2 and 3 of yours.
For Point 2: Kindly see page 37/46- Role and Choice of Reference Formulation for Deconvolution. Immediate release formulations can be used as RFDs in IVIVC studies and will also allow adequate approximation of the in vivo drug release from the MR formulations as long as the rate of dissolution from the IR formulation is fast relative to its absorption (which is normally the case for the drugs that are chosen as suitable for MR product development).
Point 3: I guess 2 period only. Considering you are focusing on- Application for a modified release formulation of a drug that is authorised in a formulation with a different release rate, so IR and MR.
Point 4: Not aware about EPARs.
Regards,
Divyen

Apologies, but was struggling with reply point wise- so had written like this.
mittyri
★★  

Russia,
2023-02-09 23:08
(531 d 03:16 ago)

@ dshah
Posting: # 23452
Views: 1,869
 

 Deconvolution sample size and exponential terms

Dear Divyen!

thank you so much for prompt reply
please see my additional questions

❝ For Point 1: I guess, it depends on variability.

As for other studies, just CV is not enough. What are the regulatory limits then and for what metric? That phrase in MR GL seems like just exploratory analysis with descriptive statistic, since there are no predictions and no checking against set of MR formulations as we do in IVIVC

❝ For Point 2: Kindly see page 37/46- Role and Choice of Reference Formulation for Deconvolution. Immediate release formulations can be used as RFDs in IVIVC studies and will also allow adequate approximation of the in vivo drug release from the MR formulations as long as the rate of dissolution from the IR formulation is fast relative to its absorption (which is normally the case for the drugs that are chosen as suitable for MR product development).

Does it mean that exponential terms should be derived from individual models of subjects after dosing by IR product?

Kind regards,
Mittyri
dshah
★★  

India/United Kingdom,
2023-02-10 10:34
(530 d 15:50 ago)

@ mittyri
Posting: # 23453
Views: 1,796
 

 Deconvolution sample size and exponential terms

Dear Mittyri!

❝ As for other studies, just CV is not enough. What are the regulatory limits then and for what metric? That phrase in MR GL seems like just exploratory analysis with descriptive statistic, since there are no predictions and no checking against set of MR formulations as we do in IVIVC


Is the aim here to develop an IVIVC or develop a new MR formulation of drug that is already authorized in a formulation with a different release rate? I believe we are focusing on (dosing regiment)IR vs MR. So at least CV for AUC depending on matrix would be taken into consideration.

❝ Does it mean that exponential terms should be derived from individual models of subjects after dosing by IR product?


It means that same model needs to be applied to all individual to derive individual exponential terms to evaluated individual deconvoluted profile.

Regards,
Divyen
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