luvblooms ★★ India, 2008-07-22 08:43 (5728 d 03:34 ago) Posting: # 2070 Views: 7,299 |
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Dear Members Regards This is my first post to this forum We are working on a moleculae and in BE studies we found that AUC0-t= 95 (83-109) AUC0-Inf= 91 (79-105) and Cmax= 105 (95-115). In this study using Level A IVIVC correlation we got the r2value of 0.976. Now we want to have a new formulation in which we want to increase the AUC by higher initial release but now we are thinking that our Cmax can get affected too. Is there any way to predict the Cmax of the next batch using IVIVC data (regression line equation) and Dissolution profile of proposed and existing batches. Here are the datas Mean Plasma Profile Time Reference Test Dissolution profles Time Ref First (bio batch) Second (proposed) Can we predict the Cmax for the proposed batch using the the above data... Drug follows one CBM Thanks in advance Edit: reformatted using BBCodes (tabs may confuse some text-browsers). [Helmut] — ~A happy Soul~ |
martin ★★ Austria, 2008-07-23 12:24 (5726 d 23:53 ago) @ luvblooms Posting: # 2073 Views: 6,240 |
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dear luvblooms ! as far as I understand your query you expect an increase release which may be due to a) an increased absorption rate or b) an increased fraction absorpt (fraction of dose that reaches systemic circulation) in case of (a) you can predict Cmax by using pharmacokinetic modeling by estimation of parameters based on your observed data and subsequently change the absorption rate based on your assumption. in case of (b) your curve is simply shifted (on assumption of dose-proportionality) as using a different dose administered. In case of a combination of a and b you may perform pharmaockinetic modeling by studying both parameters. hope this helps martin |
luvblooms ★★ India, 2008-07-24 07:57 (5726 d 04:20 ago) @ martin Posting: # 2074 Views: 6,134 |
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dear Martin ! Thanks a lot for your precious comments But i have certain doubts again (sorry for that) ❝ (a) you can predict Cmax by using pharmacokinetic modeling by estimation of parameters based on your observed data and subsequently change the absorption rate based on your assumption Can you please tell me how to do this using this example, that would be help me understanding the problem in a better way ❝ (b) your curve is simply shifted (on assumption of dose-proportionality) as using a different dose administered We are using the same dose ❝ In case of a combination of a and b you may perform pharmaockinetic modeling by studying both parameters. How can this be done??? Thanks for your help Edit: Standard quotes restored. [Helmut] — ~A happy Soul~ |
martin ★★ Austria, 2008-07-24 11:56 (5726 d 00:21 ago) @ luvblooms Posting: # 2075 Views: 6,210 |
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dear luvblooms ! your mean concentration time profile for your preparations look like the drug is given by an extravascular route of administration (oral, rectal, ... ). 1) you have to find an adequate mathematical model for your data. as starting point you may use a simple one-compartmental open model with first order absorption and first order elimination (e.g. Gibaldi and Perrier 1982, pages 34) which has the form c = ((ka x F x D) / (V x (ka-ke))) x (exp(-ke x t)-exp(-ka x t)) where c represents the measured concentration, F represent the fraction absorbed, ka represent the absorption rate, D represents the dose administered, ke represent the elimination rate, V represent the volume of distribution and t represent the time. as you can see from this model, an increased release - on the assumption that dose, volume of distribution and elimination rate are not affected - can be caused by an increased absorption rate (ka) and/or and increased fraction absorbed (0<=F<=1). 2) estimate parameters based on observed data for an adequate model using nonlinear fitting. from a technical point of view you may have to a-priori specify V, D and F as the nonlinear fitting algorithm may not be able to distinguish between these parameter using the closed form of the model stated above (nonlinear fitting is mixture between science and art !!). 3) replace the estimated absorption rate and/or fraction absorbed (or rather the product F x D) with your assumptions and plot / re-calculate concentrations at various time points with modified parameters. using this approach you can check different scenarios and how this scenarios affect Cmax or any other concentration (summarized by the AUC). on the assumptions stated above, I think that - an increased absorption rate may affect Tmax but not Cmax - an increased fraction absorbed may affect Cmax but not Tmax (curve is simply shifted) - an increased absorption rate and an increased fraction absorbed may affect Cmax and Tmax hope this helps martin |
Helmut ★★★ Vienna, Austria, 2008-07-24 16:18 (5725 d 19:59 ago) @ martin Posting: # 2079 Views: 6,197 |
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Dear Martin! ❝ [...] I think that ❝ - an increased absorption rate may affect Tmax but not Cmax See the last plot in this post: if only k01 changes, both Cmax/tmax are affected. — 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 |
martin ★★ Austria, 2008-07-25 10:48 (5725 d 01:30 ago) @ Helmut Posting: # 2080 Views: 6,115 |
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dear hs ! thank you very much for pointing this out; your are totally right - an increased absorption rate will affect Cmax (increase) and Tmax (decrease) as the amount of the absorbed drug at a given time point will increase due to the proportionality of a first order kinetic when the elimination is unaffected. best regards martin |