luvblooms
★★  

India,
2008-07-22 08:43
(5728 d 03:34 ago)

Posting: # 2070
Views: 7,299
 

 Prediction of Cmax [Dissolution / BCS / IVIVC]

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
 0.00      0.00      0.00
 1.00    182.52     48.47
 2.00    565.79    428.95
 3.00    809.47    682.06
 4.00   1005.12    929.53
 5.00   1434.22   1353.42
 6.00   1506.14   1571.97
 7.00   1549.33   1624.28
 8.00   1645.65   1712.17
 9.00   1681.64   1797.18
10.00   1703.32   1771.66
11.00   1645.02   1740.31
12.00   1603.28   1670.32
13.00   1525.32   1615.74
14.00   1537.53   1583.79
16.00   1359.26   1379.78
24.00    734.25    594.64
36.00    167.872   151.341
--------------------------


Dissolution profles
Time Ref  First (bio batch) Second (proposed)
 0     0          0              0
 1    11          6             17
 2    18         18             26
 4    30         36             42
 8    51         58             62
12    71         71             77
16    86         81             87
20    96         90             93
24   102         96             98
---------------------------------------------

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
 

 Prediction of Cmax

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
 

 Prediction of Cmax

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
 

 Prediction of Cmax

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
★★★
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Vienna, Austria,
2008-07-24 16:18
(5725 d 19:59 ago)

@ martin
Posting: # 2079
Views: 6,197
 

 Prediction of Cmax

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.

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martin
★★  

Austria,
2008-07-25 10:48
(5725 d 01:30 ago)

@ Helmut
Posting: # 2080
Views: 6,115
 

 Prediction of Cmax

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
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