Bioequivalence and Bioavailability Forum

Alex
☆

Austria,
2012-11-29 12:45
(4603 d 01:36 ago)

Posting: # 9631
Views: 7,050

bimodal absorption process? [PK / PD]

Dear all!

I just hit upon some really strange concentration-time profiles following SC administration: It looks like that concentrations follow a bi-modal absorption process with a mixture of zero-order and first-order absorption, where first order peak (clearly smaller) follows zero-order peak with a time-lag. Elimination looks like one-compartmental first order.

Do you know some literature/references where such a pharmacokinetic model is mentioned/described? Is it straight-forward to apply NCA or should i try to fit a "fancy" model?

Thanks a lot!

Alex

Helmut
★★★

Vienna, Austria,
2012-11-29 15:23
(4602 d 22:58 ago)

@ Alex
Posting: # 9632
Views: 5,830

SC: mixed absoption

Post reply

Hi Alex!

First one assumption: You know from somewhere else (literature data: preferably IV or IR oral) that what you see after SC is the true elimination (no flip flop PK). If this is the case it might be possible that the drug precipitates to a minor extent at the injection site. A major fraction of the dose is released from the depot (zero order), but the precipitated fraction starts to dissolve after a lag-time. Then a first order would be possible.

❝ Do you know some literature/references where such a pharmacokinetic model is mentioned/described?

No.

❝ Is it straight-forward to apply NCA or should i try to fit a "fancy" model?

Both should work; it depends on what you want to achieve. ;-)

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Science Quotes

Dr_Dan ★★ Germany, 2012-11-29 16:27 (4602 d 21:54 ago) @ Alex Posting: # 9634 Views: 5,624	solution or suspension? Post reply
	Dear Alex First of all one question: sc administration of a solution or suspension? Kind regards Dan — Kind regards and have a nice day Dr_Dan

Alex ☆ Austria, 2012-11-30 09:44 (4602 d 04:37 ago) @ Dr_Dan Posting: # 9641 Views: 5,480	solution or suspension? Post reply
	Dear all! ❝ First of all one question: sc administration of a solution or suspension? It was a solution. It looks like that it is not the "true" elimination as terminal half-lifes for SC compared with IV are clearly longer. So, fitting an adequate model is the only opportunity to get valid estimators for terminal half-lifes? Thanks for your help! Alex

Helmut
★★★

Vienna, Austria,
2012-11-30 14:08
(4602 d 00:13 ago)

@ Alex
Posting: # 9642
Views: 5,511

t½ (el.) in flop flop PK

Post reply

Hi Alex!

❝ It was a solution.

❝ It looks like that it is not the "true" elimination as terminal half-lifes for SC compared with IV are clearly longer.

So you have flip flop PK (k₁₀ ≥ k₀₁).

❝ So, fitting an adequate model is the only opportunity to get valid estimators for terminal half-lifes?

If you mean estimates, yes. ;-)

The model can be quite tricky. Some hints:

For SC it might be possible that you don’t get complete absorption. Include an f_abs-parameter (≤1) in the model.
Introduce parameters for the dose-fractions (zero- and first-order parts), where fract₀ + fract₁ = 1 and fract₀ > fract₁.
Use a lag-time for the first-order part.
Consider adding a lag-time to the zero-order part of the model. In my experience SC models without a lag-time don’t fit well in some (or even most) subjects.
Use a lag-time for the first-order part.
Set up the model in such a way that the zero-order (input) rate constant = elimination of the first order part. Since the zero order part represents the major part of the dose and your apparent elimination is longer than what is know from IV, this should be good starting point. For a one-compartment first order we cannot tell which rate constant is absorption and which one is elimination. If you get bad fits, switch rate constants in the first order part (flip flop PK as well). However, I would expect the first variant to be numerically more stable.

Good luck!