Difference between actual and published PK parameters [Study As­sess­ment]

posted by Helmut Homepage – Vienna, Austria, 2022-02-15 15:56 (90 d 04:26 ago) – Posting: # 22786
Views: 591

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.



Dif-tor heh smusma 🖖 [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

UA Flag
Activity
 Admin contact
22,074 posts in 4,629 threads, 1,565 registered users;
online 9 (0 registered, 9 guests [including 8 identified bots]).
Forum time: Monday 21:22 CEST (Europe/Vienna)

Rules are for the guidance of wise men
and the blind obedience of fools.    attributed to Solon

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5