4 replies to this topic

[Chandramouli]

Hi All,

 

I have 6 formulations

A = IR (medium)

B = (fast)

C = (slow)

D1, D2, D3.  Dissolution data available for all 6 formulations. However, I dont have in vivo data for D2 and D3. Hence, I am using A to predict the PK profile for D2 and D3, can this be done?

Also, the Average %PE (for internal validation) is less 15% both cmax and auc. However, the %PE for C (cmax) is around 22%. Is the model still valid?

Parameters

Formulation

Observed

Predicted

%PE

C_max (µg/mL)

B

5.76

5.79

0.59%

 

A

4.70

4.81

2.48%

 

C

5.72

4.07

28.90%

Average %PE

 

 

 

12.70%

AUC_{inf_pred} (µg.h/mL)

B

18.57

18.80

1.23%

 

A

17.90

19.28

7.70%

 

C

16.16

15.91

1.52%

Average %PE

 

 

 

3.48%

 

[Simon Davis]

Dear Chandramouli, I'm a little confused by what you are hoping to achieve, also if you can post your project it would probably help follow your working/settings.

 

Are D1-3 supposed to be IR? which is your target? D1?

 

Are you aiming to select the most likely candidate to go forward with a pivotal study or are you applying for a biowaiver, for the latter your current model would not be valid since it fails the guidance for Cmax

I have 6 formulations

A = IR (medium)

B = (fast)

C = (slow)

D1, D2, D3.  Dissolution data available for all 6 formulations. However, I dont have in vivo data for D2 and D3. Hence, I am using A to predict the PK profile for D2 and D3, can this be done?

 

It is implied you also have in vivo data for D1, why don't you use that A, B, C as the internal sets and possibly D1 as the external set (or if that's not great then use it as an internal set to give more info to your model building).

 

Then you allow the IVIVC model to predict the in vivo profiles for D2 & D3, rather than assuming A's parameters are sufficient.

 

Simon

[Chandramouli]

Hi Simon,

Thanks for your Reply.

My target formulation is D1 and also would like to know if i can extended this formulation to D2 and D3 using A (IR) tablet.

D1 to D3 is crushed tablet mixed with a fluid (different viscosity - D1 more viscous, D2 medium viscous, D3 less viscous). These are initial studies, and we are modifying the existing IR tablet, so i guess it will be a biowaiver.

Also, we expect the Cmax to be less. Also, these formations are not officially accepted and used in a clinical practice.

As suggested by you i am using A,B,C as the internal set and D1 as an external set.

Please let me know if you need more information.

[Simon Davis]

It sounds like you've done the correlation and are getting what seem to be good predictors for AUC, but less so for Cmax.  How do predictions for D1 look if you use that in the internal set?

 

Otheriwse I am not sure how to direct you further but with the current results I doubt you can apply for a biowaiver; this suspending of a crushed tablet in viscous liquids sounds like it could be pretty variable too.

 

  Simon

[Chandramouli]

Yes you are right, variability with our dissolution data was high with D1 (hightly viscous) compared to D2 and D3. Also, in our pk data we found that the Cmax was significantly less compared with the other 3 formulations (A, B and C).

 

The prediction for D1 did not change much if i use this as an internal set. The drug relase from our dissolution study was only 60% after 3 hrs, Also, we used SGF (pH1.2) in our dissolution study, and think this is being the limitation of this study and we are in the process of working with other gastric fluids (fasted and fed SGF/intestinal fluid).

This fig below is the IVIVC PK prediction for D1.