Back to the Top
I'm new to this discussion group, but already found it extremely
I have two questions:
2. 2nd question is related to allometry.
For the same cmpd above, since I had no in vitro turnover, I had to
rely on allometry to predict human CL. The problem is that rat, dog
and MK had very different IV CL (0.1, 0.07 and 0.5 L/h/kg,
respectively). I could get a predicted CL value with the 3 species
with MLP or brain weight adjustment (~4-5 L/h). However, using MK
liver Q alone, the pred hum CL is ~16 L/h. Using Tang H et al's
recent empirical equations in DMD, the the pred hum CL varies from
1.5-3.6; however, using Tang's empirical equation based solely on MK
PK, the value is 14 L/h. Therefore the overall range of pred hum CL
is 1.5-16 L/h. Is there any way to refine the prediction - basically
to determine whether MK or dog is an outlier...
Response(s) are very appreciated. Thanks.
Yang Xu, Ph.D.
Pharmacokinetics and Drug Metabolism
One Amgen Center Drive, MS 30E-2-C
Thousand Oaks, CA 91320-1799
Back to the Top
Based on the Clearance values you have described, rat and dog appears
to have similar clearance (~3-4% of HBF) and Monkey seems to have an
higher extraction (19% of HBF). Although one would be tempted to say
monkey as the outlier but who knows, human could behave like a monkey.
I am not sure what were the body weights of the animals, based on the
standard BW (Monkey/4, Rat/0.35 and Dog/10 kg), the following are
predictions as you described.
ROE: 0.060 L/hr/kg (BrW correction)
Rat method: 0.015 L/hr/kg
Dog method: 0.029 L/hr/kg
Monkey method: 0.204 L/hr/kg
Rat_Dog method: 0.019 L/hr/kg
Rat_Monkey method: 0.048 L/hr/kg
As it is apparent, rat and dog method provides lower estimates than
the Monkey or Rat_monkey methods because rat and dog seems to have
lower clearance than monkey, and the ROE predicts somewhere in the
middle of the range (0.019-0.204 L/hr/kg). This wide range is clearly
due to species difference and invitro data would have helped you out.
I am not sure what the protein binding looks in these species and if
that would explain the difference.
There are multiple ways you could approach this uncertainty. If you
have high exposure ratios (NOAEL/MED) then you could take some chance
with the method which predicts high clearance. Perhaps you could take
a safer approach with the lowest clearance but you may have to add few
more cohorts later to get to where you want too in clinic if you see
that you have under predicted the clearance or over predicted the
exposure. The other alternative is take a moderate approach thus
minimizing the risk associated with over or under predicted clearance.
It is difficult to decide which species is an outlier unless you have
a good understanding about metabolic and excretory pathways. Even when
you think you know everything, there is always a surprise "Vertical
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Allometry (MK or dog as an outlier)" as the subject
Support PharmPK by using the
Copyright 1995-2011 David W. A. Bourne (email@example.com)