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maulik963 ☆ India, 2016-05-31 10:09 (3206 d 20:26 ago) Posting: # 16372 Views: 3,995 |
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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. |
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Helmut ★★★   Vienna, Austria, 2016-05-31 15:14 (3206 d 15:21 ago) @ maulik963 Posting: # 16373 Views: 3,238 |
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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). — 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 |
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maulik963 ☆ India, 2016-06-02 15:45 (3204 d 14:51 ago) @ Helmut Posting: # 16380 Views: 3,110 |
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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). |
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Helmut ★★★ Vienna, Austria, 2016-06-02 16:07 (3204 d 14:29 ago) @ maulik963 Posting: # 16381 Views: 3,133 |
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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. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz