Tuesday, December 10, 2013

Pharmacokinetic studies when endogenous compounds exist and pre-dose concentrations are not zero

This Monday, FDA issued a new guidance titled “ Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA”. While the guidance is more for bioequivalence studies for generic drugs, a paragraph on Endogenous Compounds caught my eyes:

E. Endogenous Compounds
 Endogenous compounds are drugs that are already present in the body either because the body produces them or they are present in the normal diet. Because these compounds are identical to the drug that is being administered, determining the amount of drug released from the dosage form and absorbed by each subject can be difficult. We recommend that applicants measure and approximate the baseline endogenous levels in blood (plasma) and subtract these levels from the total concentrations measured from each subject after the drug product has been administered. In this way, you can achieve an estimate of the actual drug availability from the drug product. Depending on whether the endogenous compound is naturally produced by the body or is present in the diet, the recommended approaches for determining BE differ as follows:  When the body produces the compound, we recommend that you measure multiple baseline concentrations in the time period before administration of the study drug and subtract the baseline in an appropriate manner consistent with the pharmacokinetic properties of the drug.
  When there is dietary intake of the compound, we recommend that you strictly
control the intake both before and during the study. Subjects should be housed at a
clinic before the study and served standardized meals containing an amount of the
compound similar to that in the meals to be served on the pharmacokinetic sampling day.
 For both of the approaches above, we recommend that you determine baseline concentrations for each dosing period that are period specific. If a baseline correction results in a negative plasma concentration value, the value should be set equal to 0 before calculating the baseline-corrected AUC. Pharmacokinetic and statistical analysis should be performed on both uncorrected and corrected data. Determination of BE should be based on the baseline-corrected data.

When we study the therapeutic proteins, we often need to deal with the endogenous concentration issue. Studies using human plasma derived products (proteins) will always involve in the endogenous concentration issue since these therapeutic proteins are naturally occurring substances and are already present in the body. The pharmacology studies for these therapeutic proteins need to consider both the endogenous (already in the body) and exogenous (through augmentation) concentrations. In a book “Clinical pharmacology of therapeutic proteins” by Dr Mahmood, three approaches are discussed to deal with this issue:
  1. subtract the pre-dose concentration – baseline-corrected pharmacokinetic analysis
  2. using the sum of exogenous and endogenous proteins following the administration of exogenous protein – uncorrected pharmacokinetic analysis;
  3. the use of radio-labeled proteins to differentiate the exogenous proteins from the endogenous proteins.


For a bioequivalence study, it is easier to show the bioequivalence with approach #2 above.

When using baseline-corrected pharmacokinetic analyses, the accurate measure of the pre-dose concentration is important. If all possible, there should be multiple measures at pre-dose and then mean value of the pre-dose measuresments can be used as the baseline for correction.

In FDA’s Draft Guidance on Progesterone, it has the following comments regarding the baseline-correction.
 Please measure baseline progesterone levels at -1.0, -0.5, and 0 hours before dosing. The mean of the pre-dose progesterone levels should be used for the baseline adjustment of the post-dose levels. Baseline concentrations should be determined for each dosing period, and baseline corrections should be period specific. If a negative plasma concentration value results after baseline correction, this should be set to 0 prior to calculating the baseline-corrected AUC. Please analyze the data using both uncorrected and corrected data.
  
In a clinical pharmacology review document for a Factor XIII Concentrate, the sponsor presented the pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) and  also the pharmacokinetic parameters based on un-adjusted FXIII activity.


In summary, while both baseline-adjusted and unadjusted PK analyses are viable approaches in dealing with the existence of endogenous concentrations, the baseline-adjusted PK analyses are the safer approach to go. In this approach, the pre-dose concentration or average pre-dose concentration will be subtracted from all post-dose concentration measures before the PK parameters (for example AUC) are calculated.  

7 comments:

Gideon St.Helen said...

Hi, I found this post quite useful/helpful!
Thanks!

Anonymous said...

I am getting concentraions below LLOQ, so what to concsider?

please see the example below:

-1.0h = 0 (BLOQ)
-0.5h = 3 (measurable concentration)
0h = 0 (BLOQ)

so i need to take mean of the above 3 concentrations and substract it from the post concentrations or i need to substract only mean of measurable concentration i.e. 3.

please reply me on sarveshnawlu@yahoo.in

Web blog from Dr. Deng said...

for post-dose concentrations, we usually handle the BLQ as following: "Concentrations below the limit of quantification (LOQ) will be indicated by BLQ. For the purpose of calculating descriptive statistics for plasma concentrations and PK parameters, if there is only one non-BLQ value after the BLQ value, then the non-BLQ value will be set to missing. If there are more than one non-BLQ values after the BLQ value, then the BLQ value will be set to missing. All other BLQ values will be set to zero."

for pre-dose concentrations, you may follow the same rule. In your situation, taking an average of three seems to be more reasonable. I guess that the purpose of taking three pre-dose samples is for taking the average.

annalise shen said...

Hi Dr.Deng,

Thank you for your post and comments ! It is especially useful to me. I am a new biostatistician in the phase I study. Based on your comments, I have a further question.
since you mentioned in your comments " if there is only one non-BLQ value after the BLQ value, then the non-BLQ value will be set to missing.", in the above situation, how should we deal with the BLQ value, as 0 or as missing value?

Would you like to provide more vivid example?

Thanks,
Best,
Annalise Shen

annalise shen said...

Hi Dr.Deng,

Thank you for your post and comments ! It is especially useful to me. I am a new biostatistician in the phase I study. Based on your comments, I have a further question.
since you mentioned in your comments " if there is only one non-BLQ value after the BLQ value, then the non-BLQ value will be set to missing.", in the above situation, how should we deal with the BLQ value, as 0 or as missing value?

Would you like to provide more vivid example?

Thanks,
Best,
Annalise Shen

annalise shen said...

Thank you for your post and comments ! It is especially useful to me. I am a new biostatistician in the phase I study. Based on your comments, I have a further question.
since you mentioned in your comments " if there is only one non-BLQ value after the BLQ value, then the non-BLQ value will be set to missing.", in the above situation, how should we deal with the BLQ value, as 0 or as missing value?

Would you like to provide more vivid example?

Thanks,
Best,
Annalise Shen

Web blog from Dr. Deng said...

-0 h = 0 (BLOQ)
0.5h = 3 (measurable concentration)
1 h = 6 (measurable concentration)
1.5h = 2 (measurable concentration)
2 h = BLOQ
3 h = 1 (measurable concentration)
4 h = BLOQ

I guess that your situation will be like the data above. In this case, if you need to calculate AUC[0-4h], you can set the concentration at 2, 3, and 4 hours all at zero or set 2 h as missing and 4 h as zero.

You will need to pre-specify in your PK analysis plan.