- On 23 Nov 2005 at 16:08:01, Lucy Lu (lucy.hlu5.-a-.gmail.com) sent the message

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I simulated an infusion reponse using Winnolin based on a single IV

bolus data to get the Cmax value. The simulated Cmax value for 30-min

infusion was 200 uM. However, when I calculated the Cmax (the plasma

concentration after 30-min infusion) by the way described below, it

produce a 2 times higher value.

The half-life of this test compound was 0.25 hr. The plasma

concentration achieved after 30-min infusion was about 75% of the

steady state concentration value (Cpss). Cpss was 540 uM calcualted

by the steady state equation. Thus, the plasma concentration value at

30-min infusion was given at 400 uM.

My question is, what causes such a difference condisering the values

should be the same in principle? Thanks in advance for any comments.

P.S. the bolus PK of the test compund was fitting a two-compartment

modeling

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Hong (Lucy) Lu - On 23 Nov 2005 at 22:22:44, "Gordi, Toufigh" (Toufigh.Gordi.-a-.cvt.com) sent the message

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The following message was posted to: PharmPK

Hi Hong,

Your last statement provides an answer to your question. For a compound

following a bi-exponential decrease in plasma concentrations, one might

see lower initial levels than expected. This is simply due to the fact

that until you have "filled" the second compartment in the model, i.e.

its concentrations are in equilibrium with the central compartment,

plasma concentrations are declining fast. The compound is leaving the

central compartment in 2 directions: to the second compartment and

elimination. Once the infusion is continued for long enough time and the

two compartments are in equilibrium, plasma levels will move toward the

steady state.

Your question is actually very similar to another one posted last week.

I recommended the other colleague to model the data in hand and simulate

to see what concentrations would be expected and if the simulations

could explain his observations of lower initial levels. Obviously, you

have made the right move from the beginning. This is actually a good

example of the utility of modeling and simulation.

A word of caution is of course that your simulations are based on a

well-established PK model and you are not violating your model

assumptions.

Toufigh Gordi

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