Bioequivalence and Bioavailability Forum • Replicated design for a combination [Highly variable+Normal]

Naveen Kumar
☆

India,
2013-06-17 16:37
(4756 d 02:55 ago)

Posting: # 10805
Views: 6,515

Replicated design for a combination [Highly variable+Normal] [Design Issues]

Dear All,

I had read the forum's terms and conditions, also searched the threads related to my query prior to registration, As i am in protocol preparation for BA BE studies and the forum is very helpful for me and i used to visit the forum daily.

here my query is,

Shall i go for a replicated design (i.e partial or full) to a combination of drugs, in which one is highly variable and the other is a normal one.

For Eg. Valsartan and Amlodipine

Valsartan is a highly variable drug ISCV greater than 30 (suported in-house studies, AUSPAR publication and UKPAR results. amlodipine is not.

Though the FDA guidnace is sugesting for a Normal crossover design for the combination. Our submission is for EMEA.

Thanks & Regards,
Naveen Kumar.SR

jag009
★★★

NJ,
2013-06-17 19:24
(4756 d 00:08 ago)

@ Naveen Kumar
Posting: # 10806
Views: 5,362

Replicated design for a combination [Highly variable+Normal]

Post reply

Hi,

❝ Though the FDA guidnace is sugesting for a Normal crossover design for the combination. Our submission is for EMEA.

With FDA, I ran a few partial replicate studies(and have also reviewed a few while doing due diligence) for combos with 1 component being HVD (CV>30%). The mixed BE approach will enable you to run stats for RSABE and ABE anyway. With EMEA I have no clue as to whether they allow you to use partial replicate (I don't see why as long as you can provide evidence that 1 component is HVD).

See example from FDA, link

Thanks
John

Naveen Kumar ☆ India, 2013-06-18 16:53 (4755 d 02:40 ago) @ jag009 Posting: # 10810 Views: 5,308	Replicated design for a combination [Highly variable+Normal] Post reply
	Dear Mr. John, Thanks for your prompt reply, can any one sugest me, that i can go for a truncated AUC in the above design. Thanks & Regards, Naveen Kumar.SR

Dr_Dan
★★

Germany,
2013-06-19 14:04
(4754 d 05:29 ago)

@ Naveen Kumar
Posting: # 10816
Views: 5,208

Replicated design for a combination [Highly variable+Normal]

Post reply

Dear Naveen Kumar.SR

The intra-CV of Valsartan is slightly above 30% ⇒ HVD, so it could make sense to use a replicate design in order to allow widening of the acceptance range for this component (valsartan only) of the combinationproduct. However, you need to keep the following in mind:

Valsartan and amlodipin differ very much in PK profile ⇒ two different sampling schemes = many blood samples, too much for replicate design?
Amlodipin has a long elimination half life (35-50 h) ⇒ you need a two weeks wash-out phase which is not very helpful for a replicate design study.
A truncated AUC is possible but would not solve the problems mentioned above.

I hope this helps
Dan

—
Kind regards and have a nice day
Dr_Dan

Naveen Kumar ☆ India, 2013-06-21 07:19 (4752 d 12:14 ago) @ Dr_Dan Posting: # 10845 Views: 5,111	Replicated design for a combination [Highly variable+Normal] Post reply
	Thank you Dr. Dan. Regards, Naveen kumar.SR