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Hi David,
Could you please post this question?
I am doing an IV infusion experiment: infusion to the steady state. Cl=Ko/Css
For infusion period: I read from literature, about 10 fold half life
How about dose level? Low dose or high dose theoretically will not make difference, right? How should I chose the dose?
Thanks
Tao
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The following message was posted to: PharmPK
Correct, as long as the dose does not put you in such a high
concentration that you are saturating a clearance mechanism. The dose
would normally be selected on the basis of the activity of the drug and
your best estimate of an plasma EC50 or EC80 (as the case may be) that
will achieve your desired end-point.
Norman
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Hi Dean,
If you think of a concentration-time plot, the half-life of the drug decides when (i.e., the x-axis) you reach the steady state, whereas the amount you infuse decides what concentration (i.e., the y-axis) you will reach. I think infusing for 10 half-lives sounds a little too long; 4-5 times should practically take you there.
If you want to reach the steady state sooner, you can give a bolus dose and then start your infusion. The question of what concentration to aim at depends on the pharmacological effect of your drug and you may want to test a few different doses and get a good understanding of the effect. Several dosing level will also help you investigate the pharmacokinetics of your compound better. Data from such study could (should?) be used in a modeling practice, allowing you to plan future studies much more efficient.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.aaa.tgordi.com
[See http://www.boomer.org/c/p4/c06/c0604.html
for one comparment example and
http://www.boomer.org/c/p4/c19/c1906.html
for two compartment example - db]
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The following message was posted to: PharmPK
Toufigh Gordi wrote:
> I think infusing for 10 half-lives sounds a little too long; 4-5 times should practically take you there.
> I agree. But rather than relying on a guess of the half-life in practice you should take several concentrations so that you can predict how close you are to steady state and of course estimate the PK parameters.
> If you want to reach the steady state sooner, you can give a bolus dose and then start your infusion. > I disagree. A loading dose does not affect the time to steady state. If you are lucky with guessing the volume of distribution and clearance (simplest case) and the loading dose reaches concs close to steady state then this can be useful to reach the target conc earlier but it does not change the time for steady state to be approached.
Nick
-- Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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Hey Tao,
10 half-lifes would be too long, I have screened 100s of NCEs for SS-PK and I can say that 4-5 half-lifes for most of the compounds would be enough to attain the SS in plasma. High or low dose should not be a concern. You can go to the dose level based on your compound PK profile, I feel a dose of 1 mg/kg/hr generally serve the prupose.
Much regards
Yunus
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Hi,
About vancomycin levels.
I often encounter cases where a repeat serum vancomycin trough level taken about one week later is much elevated (about 2 x) than the initial level taken at almost stead state (on the second or 3rd day of q12 dosing). During this time the patient has been receiving the same dose and his SCr and weight remained stable. Does vancomycin accumulate in the tissues early on and then reach a saturation point after which time it "appears that there are more drug in the body, assuming there is no underlying renal dysfunction "? Do others observe this trend and what could be the explanation?
Thanks.
Kum Ja Lee,PharmD.
USC School of Pharmacy Los Angeles, CA 90033
kumlee.aaa.usc.edu
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Lee
Your observation is clearly borne out in the literature. Your specific =
query is difficult to answer. So you may be correct, or we may be seeing =
a change in distribution volume on therapy (leading to a change in =
clearance) or we see a reduced general clearance in the absence of =
changes in our surrogate GFR marker (SCr).
We more commonly see patients with changing RF (SCr) and I/O that may =
play into the accumulation, but not always. As a consequence, we make =
sure we reevaluate in 2-3 days before things go stupid on us.
Wish I had an answer for you, but it would take a more indepth PK =
analysis beyond just trough levels to try to sort it out.
Dale Bikin, PharmD
Banner Good Samaritan Medical Center=
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