Loky do
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Egypt,
2022-02-14 17:06
(790 d 20:09 ago)

Posting: # 22779
Views: 2,644
 

 Difference between actual and published PK parameters [Study As­sess­ment]

Dears,,

We have a Dapoxetine Bioequivalence study up to our knowledge, Dapoxetine known to have biphasic half-life; initial and terminal half-life, with plasma levels less than 5% of peak concentrations by 24 hours post-dose, The published value for initial half-life is 1.3-1.5 hours and terminal half-life is approximately 15-19 hours.

the study practical results for t1/2 was 8.8 Hours, the AUCextra/AUCobs % values for all volunteers were below 20%, resulting in AUC0-t/AUCobs% values of more than 80%; hence, the sampling times’ intervals and concentrations were sufficient to detect extent of drug absorption. Also, the limit of detection was from 5.00 – 1000 ng/mL, as the LLOQ represented 1% of practical results of practical results of Cmax for test and reference products

A inquiry from the Authority on the study stating that the LLOQ of the study is not sensitive enough for accurate measuring of volunteers concentrations as the drug was detected (appear concentrations) for only 24 hours in most of the volunteers.

What is the possible causes for the difference between the actual and the published t1/2? in addition to practically when we extend the calibration curve in order to measure all volunteers concentrations, it doesn't much differ from the old result?

Also what would be the proper justification and the action to be taken in response to the authority?

Thanks in advance


Edit: Category changed; see also this post #1[Helmut]
Helmut
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Vienna, Austria,
2022-02-14 18:30
(790 d 18:45 ago)

@ Loky do
Posting: # 22780
Views: 2,291
 

 Difference between actual and published PK parameters

Hi Loky do,

❝ A inquiry from the Authority …


Out of curiosity: Which one? :-D

❝ … stating that the LLOQ of the study is not sensitive enough for accurate measuring of volunteers concentrations as the drug was detected (appear concentrations) for only 24 hours in most of the volunteers.


Why the heck? You covered more than 80% of AUC0–∞.

❝ What is the possible causes for the difference between the actual and the published t1/2?


No idea. More common are cases like this one (slides 16–21), i.e., due to a more sensitive method the half life is longer than reported in literature. If your method was validated, I don’t see any reason to question the outcome of the study.

❝ in addition to practically when we extend the calibration curve in order to measure all volunteers concentrations, it doesn't much differ from the old result?


That would require a least a partial revalidation.
BTW, method validation should not be considered as an end in itself. It serves a purpose. You were already able to describe the extent of absorption sufficiently enough. IMHO, it would be just a waste of time, resources, and money only to bring the extrapolated AUC down to say, <5% instead of <20%.

❝ Also what would be the proper justification and the action to be taken in response to the authority?


I’m not good in diplomatic answers to stupid questions. Sorry.

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Loky do
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Egypt,
2022-02-15 14:20
(789 d 22:55 ago)

@ Helmut
Posting: # 22783
Views: 2,162
 

 Difference between actual and published PK parameters

Thanks Helmut for your reply ;-), excuse my confusion, I have a question regarding dapoxetine biphasic half-life; the initial and terminal half-life (the initial half-life which is 1.3-1.5 hours and the terminal half-life which is 15-19 hours) does this biphasic nature affect the practical obtained half life of the drug? and is this nature could affect the drug variability?

Thanks
dshah
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India/United Kingdom,
2022-02-15 16:26
(789 d 20:49 ago)

@ Loky do
Posting: # 22784
Views: 2,181
 

 Difference between actual and published PK parameters

Dear Loky do!

❝ does this biphasic nature affect the practical obtained half life of the drug? and is this nature could affect the drug variability?


The biphasic nature (compartmental analysis) would not affect your outcome for BE as NCA is recommended by regulatory bodies. Although as per AusPAR- there is no significant impact of age and Race, your half-life is different than the reported one. Kindly refer pg 27-34 of AusPAR.

Regards,
Dshah
Loky do
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Egypt,
2022-02-15 16:48
(789 d 20:27 ago)

@ dshah
Posting: # 22785
Views: 2,188
 

 Difference between actual and published PK parameters

❝ Dear dshah


agree with ElMaestro, I noticed that subjects with shorter half-lives (about 50% of total study subjects) have lower plasma concentration than other subjects with longer half-lives, this could support the fact of fast and slow metabolizers as https://www.medicines.org.uk/emc/product/1269/smpc, also I noticed that those subjects weight is lower than others with long half-lives? could it be a proper justification?

Thanks dears
Helmut
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Vienna, Austria,
2022-02-15 16:56
(789 d 20:19 ago)

@ Loky do
Posting: # 22786
Views: 2,202
 

 Difference between actual and published PK parameters

Hi Loky do,

❝ […] I have a question regarding dapoxetine biphasic half-life; the initial and terminal half-life (the initial half-life which is 1.3-1.5 hours and the terminal half-life which is 15-19 hours) does this biphasic nature affect the practical obtained half life of the drug?


I don’t understand what you mean by ‘practical obtained half life’. Do you mean the apparent terminal half life estimated from a lin/log-regression? Let’s explore the fasted study of Yan et al.:

[image]


Here we see a straight line starting at 12 hours. Therefore, we can reliably estimate \(\small{\lambda_\textrm{z}}\).

Since you wrote in your original post

❝ ❝ ❝ the drug was detected […] for only 24 hours in most of the volunteers.

it might well be that distribution was not complete ≤ 12 hours and hence, the estimated elimination contaminated. When I make a rough estimation from the concentrations in the figure between 8 and 24 hours, I get a half life of ~9.6 hours. Not exactly yours, but close.

Possibly you see such patterns (+ – +) in the fits:

[image]


Of course, what ElMaestro wrote might be another explanation.

However, in BE we are interested in detecting potential differences in the absorption of formulations. Once absorption is complete,* anything else is a property of the drug and should not be a regulatory concern.

❝ and is this nature could affect the drug variability?


In BE we make the – rather strong – assumption that clearance is constant (background). If this is not the case (likely…), it will negatively affect the residual variability.
In a two-compartment system, we have three clearances: The total body clearance (associated with elimination) and two inter-compartment clearances (associated with distribution). If you are in church of volumes of distribution / rate-constants:$$\begin{matrix}
\overset{k_\textrm{a}}{\longrightarrow} & \boxed{V_1} & \overset{k_{12}}{\underset{k_{21}}{\rightleftharpoons}} & \;\;\boxed{V_2}\\
& \phantom{0}\downarrow \tiny{k_\textrm{e}} & &
\end{matrix}$$ In simple terms: We can expect that in a multicompartment system the between-occasion variability to be larger than in a one-compartment system.


  • Speaking of IR formulations. Once we are crossing the Rubicon of flip-flop PK (\(\small{k_\textrm{a}\leq k_\textrm{e}}\) is common for prolonged release formulations), we have to follow the profile much longer.

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dshah
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India/United Kingdom,
2022-02-14 19:39
(790 d 17:35 ago)

@ Loky do
Posting: # 22781
Views: 2,240
 

 Difference between actual and published PK parameters

Hi Loky do:

❝ the study practical results for t1/2 was 8.8 Hours, the AUCextra/AUCobs % values for all volunteers were below 20%, resulting in AUC0-t/AUCobs% values of more than 80%; hence, the sampling times’ intervals and concentrations were sufficient to detect extent of drug absorption. Also, the limit of detection was from 5.00 – 1000 ng/mL, as the LLOQ represented 1% of practical results of practical results of Cmax for test and reference products


I agree with Helmut.
I believe that as per regulatory guideline- we are doing NCA for BE determination over compartmental analysis, so unless your AUCt/AUCinf>0.8 which determines that sampling time point (extent of exposure) of and analytical method are capable enough captures appropriate elimination half life.
I believe that one another alternative could be to take available literature of BE and determine BE with AUC0-24. Over here- make sure that AUC0-24/AUCinf>0.8 for that literature and justify that lowering the LLOQ may not be useful as you have already meet the regulatory requirement.
Kindly go through- doi:10.1002/cpdd.866. As per the article, the mean profile is given below:

[image]

The GMR along with 90% CI is given below:

[image]

Although you may not have individual data, make a point that AUC0-24/AUCinf>0.8.
Ideally you are meeting the regulatory requirement.
Regards,
Dshah
ElMaestro
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Denmark,
2022-02-15 00:09
(790 d 13:06 ago)

@ Loky do
Posting: # 22782
Views: 2,336
 

 Difference between actual and published PK parameters

Hi Loky do,

I don't think I can disagree with anything dhsah and Helmut wrote, but in addition to their comment I'd like to point out that this is a drug metabolised by CYP2D6 and 3A4. You might indeed see some differences across races. If the study you are comparing with was done in a population a little different from yours then chances are that you'd see different elimination constants etc.
Check the SPC. Don't be fooled by the innocent remark about race differences. Jump instead to the remark about polymorphism. If you are not certain that the t½ reported came from a population similar to yours then I'd conveniently throw the race factor on the table as a likely potential reason for PK-differences.

Pass or fail!
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