jag009
★★★

NJ,
2020-02-03 20:15

Posting: # 21132
Views: 743
 

 Study which captures SD and SS PK Profiles [Design Issues]

Hi all,

I seek your opinion on the follow:
If you are being asked to design a PK study to capture single dose and SS PK profiles for a drug product, which dosing and sampling design would you use?
A) On Day 1 dosing, PK sample from time 0 to X (wait a day to a few days or whatever so to capture 1/2 life). Repeat dosing for x number of days to hit steady state (while collecting predose samples to assess SS), then capture SS pk profile from 0 - x hours as per dosing interval (if dosing interval 6 hours then stop at 12 hrs).
B) Capture day 1 PK from time 0 to end of dosing interval, repeat dosing for x # of days (base on dosing interval) to hit SS. On last day of dosing capture time 0 - x (x = whatever hrs needed to fully capture the elimination phase + half-life).

I have seen both designs but I (and my former bosses) prefer method A. The only drawback I see from A is it takes longer time.

Thx
J
mittyri
★★  

Russia,
2020-02-03 21:05

@ jag009
Posting: # 21136
Views: 492
 

 A vs B

Hi John,

citing our Hero:

If one is really interested in λz and has no SD-phase in the study, sampling should continue until concentrations from previous doses are washed out – I would expect any estimate within the MD-profile to be biased towards faster elimination.

» I have seen both designs but I (and my former bosses) prefer method A. The only drawback I see from A is it takes longer time.

why does A take longer time?


Edit: Changed to internal link; see also this post #7[Helmut]

Kind regards,
Mittyri
jag009
★★★

NJ,
2020-02-03 21:29

@ mittyri
Posting: # 21137
Views: 486
 

 A vs B

Thanks Mittyri,

» citing our Hero:

Can you try the above link? I tried and I got some 404 error...

» » I have seen both designs but I (and my former bosses) prefer method A. The only drawback I see from A is it takes longer time.
» why does A take longer time?

Sorry I made a mistake. Retracting my statement (above).
john


Edit: Link corrected. [Helmut]
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2020-02-04 00:57

@ jag009
Posting: # 21138
Views: 464
 

 ANDA or NDA?

Hi John,

» If you are being asked to design a PK study to capture single dose and SS PK profiles for a drug product, which dosing and sampling design would you use?

It depends on which question you want to answer.

» A) On Day 1 dosing, PK sample from time 0 to X (wait a day to a few days or whatever so to capture 1/2 life). Repeat dosing for x number of days to hit steady state (while collecting predose samples to assess SS), then capture SS pk profile from 0 - x hours as per dosing interval (if dosing interval 6 hours then stop at 12 hrs).

Fine and the standard approach if
  1. you will analyze the data only by NCA,
  2. you know that the drug follows linear PK, and
  3. there are no circadian variations in PK (otherwise, you have to administer according to the intended dosing regimen in SS and sample for 24 hours).

» B) Capture day 1 PK from time 0 to end of dosing interval, repeat dosing for x # of days (base on dosing interval) to hit SS. On last day of dosing capture time 0 - x (x = whatever hrs needed to fully capture the elimination phase + half-life).

To characterize the PK of a new drug by PK modeling you would always go with this approach and sample as long as possible. Funky things may happen in nonlinear PK (auto-induction / -inhibition, capacity-limited elimination, …); see this example.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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mittyri
★★  

Russia,
2020-02-04 09:02

@ Helmut
Posting: # 21140
Views: 439
 

 Modelling

Hi Helmut,

» » B) Capture day 1 PK from time 0 to end of dosing interval, repeat dosing for x # of days (base on dosing interval) to hit SS. On last day of dosing capture time 0 - x (x = whatever hrs needed to fully capture the elimination phase + half-life).
»
» To characterize the PK of a new drug by PK modeling you would always go with this approach and sample as long as possible. Funky things may happen in nonlinear PK (auto-induction / -inhibition, capacity-limited elimination, …)

I don't think the proposed scheme is good enough for modelling such difficult things. There are no Ctau's planned. Moreover, I would mix the A and B for that purpose.

And sorry for a broken link, I cannot carve in my mind that tags for years :-D

Kind regards,
Mittyri
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2020-02-04 12:17

@ mittyri
Posting: # 21143
Views: 410
 

 Modelling

Hi mittyri,

» I don't think the proposed scheme is good enough for modelling such difficult things. There are no Ctau's planned.

Correct, pre-dose values are required. I overlooked that in John’s post.

» Moreover, I would mix the A and B for that purpose.

Stop sampling in SS at 6 (or even 24 hours)? I wouldn’t do that. You might not be able to estimate deeper compartments from SD due to analytical limitations.

» And sorry for a broken link, I cannot carve in my mind that tags for years :-D

No worries.

Cheers,
Helmut Schütz
[image]

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

Russia,
2020-02-04 12:38

@ Helmut
Posting: # 21144
Views: 404
 

 Modelling: SD+SS

Hi Helmut,

» » Moreover, I would mix the A and B for that purpose.
» Stop sampling in SS at 6 (or even 24 hours)?

I mean to sample as long as possible in SD and SS both

Kind regards,
Mittyri
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