maulik963
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India,
2016-05-31 10:09
(2858 d 20:55 ago)

Posting: # 16372
Views: 3,403
 

 Partial AUC & Cmax in case of multiphasic modified release drug product [Regulatives / Guidelines]

Dear All,

I wish to conduct a 2-way crossover study on multiphasic modified release drug product for EMEA submission.

The drug product is a prolonged release formulation with biphasic release pattern (IR+MR). The initial maximum concentration achieves at about 1 to 2 hours (due to release of IR Part) and Peak plasma concentration achieves at about 6 to 8 hours.

As per "Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms_Jun-2015", For single dose study of multiphasic modified release drug product following parameters has to show bioequivalence.
AUC0-t, AUC0-∞, partialAUCs and Cmax in all phases.

I have kept AUC0-t, AUC0-∞, partialAUC0-2, partialAUC2-t.

Please provide your opinion on following points.

(1) Please help to understand the meaning of "Cmax in all phases".
Shall I consider it as Cmax(0-2) & Cmax(2-t)? OR shall I consider Cmax(0-t)?
Shall I report the result for Cmax(0-2) & Cmax(2-t) and prove bioequivalence only on Cmax(0-t)?

(2) As per the guideline, Cmax(x+1) and partialAUC(x+1) also need to be evaluated. In this case shall I consider it as Cmax(2+1) = Cmax0-3 & partialAUC(2+1) = partialAUC(0-3)? Please help to understand the rationale of Cmax(x+1) & partialAUC(x+1).

Thanks in advance.
Helmut
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Vienna, Austria,
2016-05-31 15:14
(2858 d 15:50 ago)

@ maulik963
Posting: # 16373
Views: 2,800
 

 The x unveiled

Hi Maulik,

❝ The drug product is a prolonged release formulation with biphasic release pattern (IR+MR). The initial maximum concentration achieves at about 1 to 2 hours (due to release of IR Part) and Peak plasma concentration achieves at about 6 to 8 hours.


❝ […] For single dose study of multiphasic modified release drug product following parameters has to show bioequivalence.

❝ AUC0-t, AUC0-∞, partialAUCs and Cmax in all phases.

❝ I have kept AUC0-t, AUC0-∞, partialAUC0-2, partialAUC2-t.


Correct.

❝ (1) Please help to understand the meaning of "Cmax in all phases".

❝ Shall I consider it as Cmax(0-2) & Cmax(2-t)?


Yes. Pre-specified cut-off time 2 hours. Hence, 1st phase ≤2 hours and 2nd phase >2 hours. You have to demonstrate BE for both.

❝ (2) As per the guideline, Cmax(x+1) and partialAUC(x+1) also need to be evaluated. In this case shall I consider it as Cmax(2+1) = Cmax0-3 & partialAUC(2+1) = partialAUC(0-3)?


No. The “x” in the table of Section 6.8.2.1 is an index denoting the phase – not a time point. In your case: Cmax(1) = Cmax(0–2), Cmax(2) = Cmax(2–t), partialAUC(1) = partialAUC0–2, partialAUC(2) = partialAUC2–t – exactly as you correctly guessed in the beginning of your post.

For most biphasic products the first phase is critical in terms of variability. Consider reference-scaling (both Cmax and partial AUC).

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maulik963
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India,
2016-06-02 15:45
(2856 d 15:19 ago)

@ Helmut
Posting: # 16380
Views: 2,679
 

 The x unveiled

Dear Helmut,

Thanks for the reply. As I understood, Cmax(x) denotes for an Immediate release phase of the formulation and Cmax(x+1) denotes for the modified release phase of the formulation. Please correct if I am wrong.

In addition to Cmax(0-2) & Cmax(2-t), shall I consider Cmax(total) [i.e. Cmax(0-t)] to demonstrate BE?

Based on the above discussion shall I keep below PK parameters to demonstrate BE?
AUC0-t, AUC0-∞, partialAUC(0-2), partialAUC(2-t), Cmax(0-2), Cmax(2-t) & Cmax(0-t).
Helmut
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Vienna, Austria,
2016-06-02 16:07
(2856 d 14:57 ago)

@ maulik963
Posting: # 16381
Views: 2,691
 

 Biphasic: x=2

Hi Maulik,

❝ As I understood, Cmax(x) denotes for an Immediate release phase of the formulation and Cmax(x+1) denotes for the modified release phase of the formulation.


In your case (biphasic), yes. The guideline deals with multiphasic formulations. Hhence, x>2 is possible.

❝ In addition to Cmax(0-2) & Cmax(2-t), shall I consider Cmax(total) [i.e. Cmax(0-t)] to demonstrate BE?


No. In my studies I only reported it.

❝ Based on the above discussion shall I keep below PK parameters to demonstrate BE?

❝ AUC0-t, AUC0-∞, partialAUC(0-2), partialAUC(2-t), Cmax(0-2), Cmax(2-t) & Cmax(0-t).


Exactly. Good luck for demonstrating BE of seven PK-metrics…


PS: If you crosspost (e.g., to David’s PKPD-list) link to this thread as well. Helps others “over there” to see what’s going on.

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