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The following message was posted to: PharmPK
Can anyone give me an example of a particular drug or a documented
instanced where increasing a drug target or a receptor can affect the
observed systemic PK? In theory, one would suspect that increasing the
target could alter apparent volume and clearance (i.e., increase V and
decrease CL), as the drug would be "sequestered" at these targets. Any
references someone can point me towards?
Burgess B. Freeman, III, PharmD
Director, Clinical Pharmacology Core
Assistant Member, Drug Development Division
Nevada Cancer Institute
10441 West Twain Avenue, Room 3196
Las Vegas, NV 89135
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Please search PUBMED or Medline for papers under the heading "Target
Mediated Drug disposition" and the authors Levy G, Mager D, Jusko WJ
& Krzyzanski W. The most thorough paper was published in JPP which
detailed the method for modeling the TMDD data for 3 example drugs.
These models apply very well to peptide and protein pharmaceuticals.
Mats Karlsson published a 1999 DMD paper for paclitaxel (if I
remember correct) explaining how to implement these complicated
models in NONMEM i.e. using ADVAN9.
Interestingly, for TMDD systems Vss will decrease as dose increases.
For CL, depending on whether the receptor sequestration leads to drug
degradation or not, CL will either decrease or stay unchanged with
increasing dose. Again, the paper in JPP performs simulations and
shows the pattern of these disposition parameters with changing dose.
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