asjrm
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UK,
2017-11-19 00:44

Posting: # 17988
Views: 6,761
 

 Single PK parameters from multiple PK parameters [PK / PD]

Hi
I am conducting a PK study where multiple doses are given morning and night for 14 days and blood concentrations are measured at pre-dose, 0.5,1,2,3,6,12,24 hours on day 15. The last dose is given on day 15 morning.
The researcher wants me to estimate the PK parameters of the single dose from the blood concentrations of multiple dosing.
is this possible?

Thank you in advance.


Edit: Category changed; see also this post #1. [Helmut]
jag009
★★★

NJ,
2017-11-19 06:32

@ asjrm
Posting: # 17989
Views: 6,164
 

 Single PK parameters from multiple PK parameters

» The researcher wants me to estimate the PK parameters of the single dose from the blood concentrations of multiple dosing.
» is this possible?

1) Do you know the half-life of this drug?
2) Was there drug accumulation?
3) Is the elimination kinetic complicated (i.e, biphasic elimination)

J
Helmut
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Vienna, Austria,
2017-11-19 10:24

@ asjrm
Posting: # 17991
Views: 6,198
 

 PK parameters from multiple doses

Hi Jeewaka,

» […] a PK study where multiple doses are given […] to estimate the PK parameters of the single dose from the blood concentrations of multiple dosing.
» is this possible?

Not easy. You could only perform modeling assuming (!) linear PK (clearance will not change over time). Given your sampling schedule I guess it will be very difficult to model anything beyond a simple one compartment model (e.g., ≥2, Michaelis-Menten elimination, circadian rhythms influencing the PK after the morning/evening doses, saturation of metabolising enzymes after accumulation, auto-induction or inhibition …). Even then you get only PK parameters describing the overall behaviour of the drug – not “of the single dose”. See this example of auto-induction (slides 21–22). With your sampling schedule I guess it would be impossible.* Next time I strongly suggest to sample at the pre-doses to get an idea. Much better to sample after the first dose as well.

   The combination of some data and an aching desire
for an answer does not ensure that a reasonable answer
can be extracted from a given body of data.
    John W. Tukey



  • You can come up with a couple of models assuming something (i.e., to avoid over-parameterisation). Very difficult to decide which one describes the PK “best”.

Cheers,
Helmut Schütz
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Yura
★    

Belarus,
2017-11-21 11:48

@ Helmut
Posting: # 17997
Views: 6,120
 

 PK parameters from multiple doses

Hi Helmut
AUC is truncated with an interval of reception (in the morning and in the evening - 12 hours).
what 24 hours? if after the first dose - it is also 12 hours. Perhaps, the AUCt / AUCi criterion will be less than 80%.
Thank you
SDavis
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Homepage
UK,
2017-11-24 10:59

@ Helmut
Posting: # 18000
Views: 6,015
 

 PK parameters from multiple doses

I would echo Helmut's comments regarding the assumptions you would have to make and convey to your audience; probably I would try to build a compartmental PK model and then simulate a profile for Day 1.

Simon

Simon
Senior Scientific Trainer
Pharsight - A Certara™ Company
Simon Davis at LinkedIn
https://www.certara.com/training/training-your-way
https://support.certara.com/forums/
Problems are not stop signs, they are guidelines. Robert H. Schuller
nobody
nothing

2017-11-24 16:07

@ SDavis
Posting: # 18001
Views: 5,978
 

 PK parameters from multiple doses

» I would echo Helmut's comments regarding the assumptions you would have to make and convey to your audience; probably I would try to build a compartmental PK model and then simulate a profile for Day 1.

If you built a model based on sampling on Day 15 only, you also have to assume linear PK/no induction. So why not simply use Cl = dose/AUC instead? :-)

Kindest regards, nobody
SDavis
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Homepage
UK,
2017-11-24 22:09

@ nobody
Posting: # 18003
Views: 6,051
 

 PK parameters from multiple doses

If I assume linear PK etc, with a model I can estimate all PK parameters e.g. Cmax, etc on Day 1. It is also possible you might not be at steady state on Day 15, if you have a long half-life.

Simon.

Simon
Senior Scientific Trainer
Pharsight - A Certara™ Company
Simon Davis at LinkedIn
https://www.certara.com/training/training-your-way
https://support.certara.com/forums/
Problems are not stop signs, they are guidelines. Robert H. Schuller
nobody
nothing

2017-11-27 14:13

@ SDavis
Posting: # 18013
Views: 5,794
 

 PK parameters from multiple doses

I see that quite often people thinking that a "model" can "extract" hidden information from their data, which is not really there (except for a number of implicit assumptions made). Would love to see the CI for the single dose Cmax predicted from Day 15 data. And some real-life data for single-dose PK. ;-)

Kindest regards, nobody
SDavis
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Homepage
UK,
2017-11-28 11:34

@ nobody
Posting: # 18017
Views: 5,790
 

 PK parameters from multiple doses

Oh I agree they are estimates, but no more so than the AUC assumption you're making with NCA, possibly less so as I am not assuming Day 15 is at steady state.

Simon
Senior Scientific Trainer
Pharsight - A Certara™ Company
Simon Davis at LinkedIn
https://www.certara.com/training/training-your-way
https://support.certara.com/forums/
Problems are not stop signs, they are guidelines. Robert H. Schuller
nobody
nothing

2017-11-28 11:51

@ SDavis
Posting: # 18018
Views: 5,810
 

 PK parameters from multiple doses

Without ANY prior knowledge on the compound:

Assume you have data only for Day 15. Samples obtained on this single day (24 h), no subsequent sampling. If the t1/2 is SO long that you havn't reached steady state by Day 15, no chance to describe this t1/2 (with model or otherwise) reliable from data obtained within 24 h sampling period. ;-)

But as long as we have no idea on the prior knowledge on the compound/formulation we are talking about, all this is somewhat academic :-D

Kindest regards, nobody
SDavis
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Homepage
UK,
2017-11-28 11:54

@ nobody
Posting: # 18019
Views: 5,775
 

 PK parameters from multiple doses

true, I forgot no subsequent sampling after Day 15, perhaps it's not too late for OP to request an extra PK analysis, they may still be coming in for a follow up visit ;0)

Simon
Senior Scientific Trainer
Pharsight - A Certara™ Company
Simon Davis at LinkedIn
https://www.certara.com/training/training-your-way
https://support.certara.com/forums/
Problems are not stop signs, they are guidelines. Robert H. Schuller
nobody
nothing

2017-11-21 14:54

@ asjrm
Posting: # 17998
Views: 6,133
 

 Single PK parameters from multiple PK parameters

Assuming you are in steady-state on day 15 (and linear PK/no induction, of course), the AUC over the dosing interval on Day 15 should equal the AUC0-oo of a single dose.

To estimate the Cmax following single-dose you would need to sample on Day 1 imho...

Kindest regards, nobody
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