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mittyri ★★ Russia, 2019-09-03 00:15 (1927 d 15:52 ago) Posting: # 20531 Views: 6,042 |
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Dear All! recently I got a question from my colleague and I didn't find good answer. Maybe you can help. Suppose there's a data from MD study for IR formulation and the model built is good enough for the data description. Now you get another dataset (SD) with the same analyte but MR formulation. Trying to build the model you figure out that the parameters differ significantly (both Cl and V). What could be a reason of that observation? We know that the kidneys do not care about lineage of entity. — Kind regards, Mittyri |
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jag009 ★★★ NJ, 2019-09-03 18:07 (1926 d 21:59 ago) @ mittyri Posting: # 20532 Views: 5,134 |
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Hi, 1) Is the MR equivalent to IR with respect to AUC? 2) How different is the Cl and V (V in particular)? 3) how good is the model fit? J |
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mittyri ★★ Russia, 2019-09-03 18:54 (1926 d 21:13 ago) @ jag009 Posting: # 20534 Views: 5,166 |
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Hi John, ❝ 1) Is the MR equivalent to IR with respect to AUC? No, MR AUC < IR AUC ❝ 2) How different is the Cl and V (V in particular)? more than 10 times ❝ 3) how good is the model fit? Internally validated with another piece of data. CV is less than 20% for all parameters Tried to use IR params for MR dataset, during convergence they are going away. The problem is not in the model fit by itself — Kind regards, Mittyri |
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ElMaestro ★★★ Denmark, 2019-09-03 19:43 (1926 d 20:23 ago) @ mittyri Posting: # 20535 Views: 5,140 |
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Hi mittyri, ❝ recently I got a question from my colleague and I didn't find good answer. Maybe you can help. ❝ Suppose there's a data from MD study for IR formulation and the model built is good enough for the data description. ❝ Now you get another dataset (SD) with the same analyte but MR formulation. Trying to build the model you figure out that the parameters differ significantly (both Cl and V). ❝ What could be a reason of that observation? You have a difference in the absorbed fraction from the two formulations which screws everything up. ❝ We know that the kidneys do not care about lineage of entity. What is meant with this term?? — Pass or fail! ElMaestro |
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mittyri ★★ Russia, 2019-09-03 20:05 (1926 d 20:02 ago) @ ElMaestro Posting: # 20536 Views: 5,201 |
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Hi ElMaestro, ❝ You have a difference in the absorbed fraction from the two formulations which screws everything up. could you please explain what is happening here? Does it mean that changes in absorbed fraction did significantly modified PK of the drug? Are there any examples for another drugs where it was already observed? ❝ ❝ We know that the kidneys do not care about lineage of entity. ❝ What is meant with this term?? Well, nothing special. I mean clearance does not depend on the route of administration for particular drug (or type of formulation). But it seems to me that due to low absorption rate by time unit the PK properties of the analyte could be closer to some low dose IR (where non-linear kinetics rules). Is that correct? — Kind regards, Mittyri |
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Helmut ★★★   Vienna, Austria, 2019-09-07 15:03 (1923 d 01:04 ago) @ mittyri Posting: # 20552 Views: 5,100 |
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Hi mittyri, ❝ […] data from MD study for IR formulation […] another dataset (SD) […] but MR formulation. Trying to build the model you figure out that the parameters differ significantly (both Cl and V). ❝ What could be a reason of that observation? Flip-flop PK? Rather the rule than an exception with MR formulations. You might run into parameter-identifiability issues. Unless you have data from an IV dose you don’t know what the true elimination is. An idea: Parameterize models with rate-constants (instead of CL) and compare kel of the IR formulation with ka of the MR formulation. Are they similar? — 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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mittyri ★★ Russia, 2019-09-08 00:25 (1922 d 15:41 ago) @ Helmut Posting: # 20553 Views: 5,066 |
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Hi Helmut, ❝ An idea: Parameterize models with rate-constants (instead of CL) and compare kel of the IR formulation with ka of the MR formulation. Are they similar? as always - thanks for support and suggestion! You know MR is a nightmare for ka modelling (that's why we go into one stage IVIVC sometimes). For that particular case absorption was modelled with a transit compartments chain. So there's no simple Ka to compare... — Kind regards, Mittyri |
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Helmut ★★★ Vienna, Austria, 2019-09-08 12:56 (1922 d 03:11 ago) @ mittyri Posting: # 20554 Views: 5,034 |
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Hi mittyri, ❝ You know MR is a nightmare for ka modelling […]. For that particular case absorption was modelled with a transit compartments chain. So there's no simple Ka to compare... OK, clearer now. Keep in in mind that CL, V, rate constants belong to the – purely empiric – (Pop)PK concept. I think that when you wrote ❝ ❝ ❝ ❝ ❝ We know that the kidneys do not care about lineage of entity. There are no organs associated with any of the PK parameters.* See also this post and read the heated debates of the two churches at David Bourne’s PKPD-list. You have models describing IR and MR. Don’t worry about ‘differences’ in CL/V. Since CL/V in both models are purely empiric and have no connection to physiology at all, be happy and go ahead. If you are interested to explore what’s going on, IMHO, the only way out would be PBPK – which is not another league but another sport. Remember that all models are wrong; ❝ ❝ ❝ […] due to low absorption rate by time unit the PK properties […] could be closer to some low dose IR (where non-linear kinetics rules). Is that correct? I don’t think so. Generally it is the other way ’round. Nonlinear PK at high concentrations (due to saturation) gets linear at low ones. Think about C2H5OH. 
— 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