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Author Topic: Drug levels  (Read 1558 times)

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Offline Cliff

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Drug levels
« on: August 14, 2006, 10:20:11 AM »
In reading the summary results for a study that documents the adequacy of drug levels for Kaletra and Reyataz (when used together), it appears that drug levels vary significantly for "C(min) values."  It doesn't say what the minimum level needed for viral suppression, and I have no idea what "C(min) values)" is, but it sounds like the level of drugs in your blood at its lowest state (maybe just before you took your next dose).
The study says this about Reyataz levels...
No difference was observed for ATV AUC0-24 or C(max) between arms A and D. ATV C(min) values were 1.07 (0.61-1.79) in arm A and 0.58 (0.32-0.83) in arm D (P = 0.001).
If I'm reading this correctly, (probably not), that would suggest that in Arm A the ("C(min) values"....again, I don't know what this means, but let's call it average values at low points) for Reyataz drug levels was 1.07, with a range of .61 to 1.79.  That's a big range.  Ignoring distribution, (it could just be one or two people in those outliers), that suggest that drug levels ranged from a low of 57% to a high of 167% of the "average."  And that the difference between the low (is this above the level needed for replication suppression?) and the high is 293%.

These levels were then compared to another group of patients and though the study concluded that there was no difference in drug levels, the "average at low" drug levels for the 2nd group was .58, which is 54% lower than the "average" for the 1st group.  And the range of the 2nd group was from .32 to .83.  Again the range (outliers) are about half as much as the first group.

How much do we know about drug levels for each patient, and how much does that contribute to drug resistance, even with appropriate adherence?


Offline newt

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Re: Drug levels
« Reply #1 on: August 14, 2006, 11:21:16 AM »
This is an interesting and sometimes important technical question.

First some PHARMOKINETIC TERMS... (pharmo = drug, kinetic = movement)

Cmax = the maximum drug concentration. Cmin = the minumum eg at the end of a dose.  Sometimes Cmin is called Ctrough.

AUC = area under the curve.  This represents the total exposure to a drug over a give period.  This is a curve because you can plot the rise and fall of the drug level on a graph, going up after a dose is taken, the slowly down as the drug is excreted.  Sometimes this comes with a time period. AUC0-24 = drug exposure over 24 hrs, AUC0-12 = over 12 hours.

Besides drug concentration the other important unit is time - tmax = time to maximum concentration of a drug after taking a dose, t1/2 = drug half life, or strictly speaking time taken for the drug concentration to go down by half (also called plasma half-life), tmin (or wrongly but often t0) is the time from taking a dose to reaching the minimum drug concentration - this is usually a range (cos people process drugs differently).

The minimum effective concentration for atazanavir is 150-850 ng/mL, or in the units used in the study you link to 0.15-0.85 microg/mL (see for example Responses to atazanavir, Kaletra and side effects for more data).

Yes, protease inhibitor (& other) drug levels vary significantly between people, and for that matter within people depending on what they've eaten, genetic background etc etc.  This may be one reason why some people who take the standard dose of drugs on time all the time get resistance (because the drug concentration has been too low to supress the virus completely). The target is to get a minumum concentration that's always effective at supressing the virus while getting a maximum that doesn't cause side effects.

For people interested in this topic, Professor David Back from the University of Liverpool has put together a very useful slideset Essential Pharmacokinetic Principles for Understanding ART which covers basic principles plus more stuff I've not mentioned like drug half-lifes, clearance rates, volume of distribution etc etc. This is part of the the HIV Drug Interactions website.

This ATP report on therapeutic drug monitoring (PDF download) is 6 years old but contains a good introduction to pharmokinetics and the science of monitoring drug levels, plus it has lots of handy pictures to explain the ideas.

- matt

« Last Edit: August 14, 2006, 12:17:36 PM by newt »
"The object is to be a well patient, not a good patient"

Offline Cliff

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Re: Drug levels
« Reply #2 on: August 15, 2006, 03:48:09 AM »
Based on this "150-850 ng/mL," the minimum concentation levels of Group D is well above that.  Which I suppose makes sense, or else the drug wouldn't have been approved.

Thanks, good stuff mister.


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