Bioequivalence and Bioavailability Forum

Hi Lakshimi,

❝ I would like to know about the PK parameters with respective to elimination rate constant.

❝

❝ generally Kel will use as a secondary parameter in PK analysis.

Given your wording I guess you are talking about NCA and not PK modeling (that’s why I changed the category of your post). In the former you calculate PK metrics and in the latter estimate PK parameters.

❝ one of regulatory audit (FDA) suggested that, u need to perform the Kel lower and Kel upper. Thereafter we are keeping the Kel lower and Kel upper parameter in the protocol …

Can you give the exact terms the FDA’s inspector used?

• k_el is not accessible in NCA – only the apparent terminal rate constant λ_z.
  For IR – if you sampled long enough – you can reasonably assume that λ_z represents elimination. In the case of flip-flop PK (most CR formulations: k_a ≤ k_el), it represents absorption.
  
• If you want to estimate k_el of an EV administration, you would need a crossover with IV and resort to PK modeling (esp. if you have >1 compartment).

I assume that the inspector meant to report the time span you used in the estimation of λ_z. BTW, never ever rely on the automatic method implemented in software! Visual inspection of fits by a pharmacokineticist (with optional correction) is mandatory.^1,2 In order to avoid bias, NCA should be performed blinded for treatment and the randomization linked to the results after locking the data base.

❝ … as well as performing the PK analysis for the both parameters.

What do you mean by that?

❝ […] what is the technical reason behind the Kel Lower and Kel upper.

Traceability of your estimations (making the life of assessors less miserable). Good practice^3,4 for decades. You will find these references quoted in standard textbooks about BE testing. Part of the output of standard PK software (e.g., in Phoenix/WinNonlin given as Lambda_z_lower and Lambda_z_upper).
For a bad example (i.e., not giving the times) see this presentation.

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1. Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development: Methods and Appli­ca­tions. New York: Wiley; 2007. p. 20–23.
   
2. Scheerans C, Derendorf H, Kloft C. Proposal for a Standardised Identification of the Mono-Exponential Terminal Phase for Orally Administered Drugs. Biopharm Drug Dispos. 2008; 29(3): 145–57. doi:10.1002/bdd.596.
   
3. Schulz H-U, Steinijans, VW. Striving for standards in bioequivalence assessment: a review. Int J Clin Pharm Ther Toxicol. 1991; 29(8): 293–8. PMID 1743802.
   
4. Sauter R, Steinijans VW, Diletti E, Böhm E, Schulz H-U. Presentation of results from bioequivalence studies. Int J Clin Pharm Ther Toxicol. 1992; 30(Suppl.1): S7–30. PMID 1601535.