Back to the Top
Dear Colleagues,
For simulating drug plasma concentration-time profile
in moderately impaired hepatic patients is there any
rule-of-thumb or rough conservative estimation as to
what percent we should reduce the clearance?
Rostam
Back to the Top
It depends, on a lot of factors.
Is the drug in question low E or high E, restrictive or non
restrictively
cleared.? What type of liver disease are you simulating? Alcoholic liver
disease involves a lot of portosystemic shunting, and therefor would
affect high E drugs the most. Hepatic toxins that destroy hepatocytes
might
be expected to affect low E drugs more, because of the dependence on
intrinsic clearance. Of course then you need to consider hypoalbuminemia
for binding changes.
I too have been thinking of constructing a model to handle all of the
above
factors. Others in the group will probably add more.
Good luck.
William R.Wolowich, Pharm.D.
Assistant Professor
Pharmaceutical Sciences
College of Pharmacy
NOVA Southeastern University
Ft. Lauderdale, FL
Back to the Top
To PK Group:
Rostam has a very interesting question. I am sure that many PK
scientists will love to do simulations for special populations
(hepatic or renal insufficiency patients or other patient groups) if
the information on change in pharmacokinetics is easily available.
This is one of the reasons why drug companies conduct clinical
studies in hepatically impaired or renally impaired patients. The
change in pharmacokinetic parameters (clearance, half-life etc.)
depends on the drug in question. The degree of liver impairment is
measured through constellation of physical findings (ascites and
encephalopathy) as well as laboratory tests (decrease in albumin,
increase in bilirubin and increase in prothrombin time). However
there may not be a good relationship between the Child Pugh score
(clinical measure of degree of liver impairment) and pharmacokinetics
of a drug. In other words there is no good way to quantitatively
predict the effect of liver impairment on pharmacokinetics of drugs
without doing actual studies. Even after obtaining the data in liver
impaired patients, the package inserts on guiding a dose is usually
nonspecific (e.g. the dose in hepatic patients should be titrated and
patients should be closely monitored).
I consulted with Dr. Richard Preston at the University of Miami in
composing a response to the question in Rostam's e-mail as we conduct
studies in special populations with this investigator. Dr. Preston
could not give an easy answer to the question.
Dyal Garg, Ph.D.
Clinical Research Services, Inc.
8838 Indian River Run
Boynton Beach, FL 33437
E-mail: Dgarg8838.-a-.aol.com
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)