I am planning a population PK/PD study for a drug with 80% unchanged renal excretion. Can serum and urine samples be combined in NLME analysis for making a PK model followed by an exposure - response analysis? As an extension - for drugs with such high renal excretion can urine be used as a primary specimen for calculation of AUC? It will be useful to me as my sample size can increase enormously if I can find a way to use urine samples from subjects for whom even a single serum sample is not available.
Can serum and urine samples be combined in NLME analysis for making a PK model followed by an exposure - response analysis?
In my opinion, which may not be popular, NLME usually relies on unrealistic PK models. So, in answer to your question, probably yes, but probably not accurately.
As an extension - for drugs with such high renal excretion can urine be used as a primary specimen for calculation of AUC?
If the sole means of elimination is renal, then yes it can. However, the urinary collection yields more AUC than a hydrophilic drug concentration curve would in plasma, and, the time scales are different as plasma dilutes by two mechanisms, passive dilution from mixing, which I call redistribution, and also by renal excretion. This produces an exaggeration of the clearance values found using plasma, and a "missing mass" problem when comparing renal clearance to the so-called total plasma clearance. Thus in certain scenarios, renal clearance is more accurate than so-called "total plasma clearance." However, another problem is that urinary collection is a lot less precise an assay method than assaying plasma dilution. Current models do not quantify redistribution properly as they spuriously assume instant mixing in one or more compartments. The alternative is to use numerical integration, and many many time-samples, starting at 5 minutes and continuing until exhaustion of concentration. This works because it in effect obviates the mixing problem, and the difference between total plasma clearance and renal clearance for renal only eliminated hydrophilic drugs is a modeling problem, not a physiologic one. For a model with more realistic mixing assumptions, there is likely no difference between plasma clearance and renal clearance. Or at least, that is what I think is going on.
Hello,
The specific details of the answer to your first question depends upon what software you are using for the NLME analysis. It will revolve around setting up a "compartment" in the model which collects the drug eliminated renally. This will then inform the estimation of the renal contribution to total clearance. Estimation of total clearance will be informed by the serum data. It's a fairly simple process.
As for the second question, that's difficult. If you can establish a good correlation between, say, amount of drug recovered in the urine during a certain time and AUC, then perhaps? Obviously renal clearance will need to correlate with total CL for this to work.
I will point out that just because a drug is "high renal extraction" does not mean it is mainly renally cleared. It just means that the kidneys are very efficient at extracting the drug, but that doesn't mean the liver isn't the main clearance pathway.
Regards,
David
Hello,
The specific details of the answer to your first question depends upon what software you are using for the NLME analysis. It will revolve around setting up a "compartment" in the model which collects the drug eliminated renally. This will then inform the estimation of the renal contribution to total clearance. Estimation of total clearance will be informed by the serum data. It's a fairly simple process.
As for the second question, that's difficult. If you can establish a good correlation between, say, amount of drug recovered in the urine during a certain time and AUC, then perhaps? Obviously renal clearance will need to correlate with total CL for this to work.
I will point out that just because a drug is "high renal extraction" does not mean it is mainly renally cleared. It just means that the kidneys are very efficient at extracting the drug, but that doesn't mean the liver isn't the main clearance pathway. The Fe indicates the importance of the kidneys to total clearance, not renal extraction ratio, or vice versa. In your case the drug is mainly reanlly cleared though (Fe = 80%).
Regards,
David
Thanks a lot Carl A Wesolowski I really understood the point here, it will certainly be incorrect to assume exact representation of Plasma concentration - time profile from urine specimens. I appreciate the time you took out to explain the point.
Hello David,
I got your point, actually I will be using NONMEM FOCE sub-routine along with R for diagnostics and pre-processing. You hit the nail when you say its possible - depending on the structural model and compartment. But I did realise that although theoretically it is possible it may not be the most physiologically plausible idea. As they say ' all models are approximations, some are meaningful'. Thanks for your response.
Just wondering if the attached article may be helpful. It shows how to avoid redistribution problems, at least for the data set examined. If you are interested in the technique, let me know.
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