Helmut ★★★ ![]() ![]() Vienna, Austria, 2020-09-09 18:21 (1321 d 19:13 ago) Posting: # 21912 Views: 3,580 |
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Dear all, at the end an For any elimination half life longer than ~7 hours and an intended dosing interval of 24 hours it will be impossible to get the MD study waived. Red are formulations with flip-flop PK (ka ≤ kel).
If the half life is short (say, 3 hours) you don’t have to dive deep into flip-flop PK and may succeed. However, such a limited extension might not match your development target.
— 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 |
wienui ★ Germany/Oman, 2020-09-09 19:43 (1321 d 17:52 ago) @ Helmut Posting: # 21913 Views: 2,975 |
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Hi Helmut, ❝ at the end an ❝ ❝ For any elimination half life of > 7 hours and an intended dosing interval of 24 hours it will be impossible to get the MD study waived. Red are formulations with flip-flop PK (ka ≤ kel). Could you please kindly add more explanation. — Cheers, Osama |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2020-09-09 21:26 (1321 d 16:08 ago) @ wienui Posting: # 21914 Views: 2,994 |
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Hi Osama, ❝ ❝ at the end an ❝ ❝ ❝ ❝ For any elimination half life of > 7 hours and an intended dosing interval of 24 hours it will be impossible to get the MD study waived. Red are formulations with flip-flop PK (ka ≤ kel). ❝ ❝ Could you please kindly add more explanation. About the script or about what I’m doing here? ![]() OK, seriously: Acc. to the EMA’s GL the MD study can be waived if AUCτ–∞ is ≤10% of AUC0–∞. Of course, in the SD study you would sample longer than τ to get a reliable estimate of λz and show that AUC0–t ≥ 80% AUC0–∞. Furthermore, you would try to show equivalence of partial AUCs. When you develop an extended release formulation you try to slow down absorption, i.e., decrease the ka/kel-ratio – which the script does. That’s all you can do cause kel is drug-specific. In an ideal case (e.g., no absorption window) the AUC will not be affected, only Cmax will be lower and delayed. So far, so good. But it has a nasty side effect. The early part of the AUC (until τ) will decrease and the late part increase, making waiving the MD study not possible due to the ≤10% of AUC0–∞ limit.*
— 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 |
PharmCat ★ Russia, 2020-09-10 22:12 (1320 d 15:22 ago) @ Helmut Posting: # 21915 Views: 2,871 |
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Hi Helmut! I can be wrong. I suppose when we have modified release dosage form there are can be some changes in the PK model. We shold take in to accaunt that dissolution profile of form in GI can have own dynamic. For example: if absorbtion of dissoluted drug is high and dissolution is linear we can have something with "plato" profile. So resulting PK profile can be wery surprising. |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2020-09-11 00:26 (1320 d 13:08 ago) @ PharmCat Posting: # 21916 Views: 2,903 |
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Hi PharmCat, ❝ I can be wrong. No, you aren’t. ![]() ❝ I suppose when we have modified release dosage form there are can be some changes in the PK model. […] So resulting PK profile can be wery surprising. In many cases a good model is similar to an infusion (i.e., zero order input). The only difference is that instead of the length of the infusion \(t_\textrm{i}\) the end of absorption \(t_\textrm{e}\) is used: $$C(t)=\frac{f\; D}{t_\textrm{e}\; V\; k_\textrm{el}}\left [\exp (k_\textrm{el}\cdot t^{*})-\exp (k_\textrm{el}\cdot t) \right ]\left\{\begin{matrix} t>t_\textrm{e} \to t^{*}=t-t_\textrm{e}\\ t\leqslant t_\textrm{e} \to t^{*}=0 \end{matrix}\right.$$Little bit tricky cause \(t_\textrm{i}\) is a known constant and \(t_\textrm{e}\) and estimate. — 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 |
PharmCat ★ Russia, 2020-09-11 04:33 (1320 d 09:01 ago) @ Helmut Posting: # 21917 Views: 2,857 |
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Hi Helmut! ❝ In many cases a good model is similar to an infusion... I thin it can be look like this: ![]() For ODE system:
function pkf!(du,u,p,t) |
mittyri ★★ Russia, 2020-09-11 07:31 (1320 d 06:03 ago) @ PharmCat Posting: # 21918 Views: 2,868 |
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— Kind regards, Mittyri |