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Hi All
I have some mice PK/PD data for an antibody drug at 2 and 8 mg/kg
weekly i.p. for 4 weeks. The PK data showed dose proportionality and
the PD effect reached saturation at these doses. After modeling using
sigmoid Emax model, I got quite different EC50 for the two doses, 11
ug/mL for the lower dose and 26 ug/mL for the higher dose.
Could someone give me some insight on why the low dose gave me higher
EC50 at saturation of response?
Thanks
Zhaoyang LI, Ph.D.
Pharmacokinetics and Drug Metabolism
Biogen, Inc.
Zhaoyang_Li.-at-.Biogen.com
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The following message was posted to: PharmPK
Zhaoyang Li wrote:
>
> I have some mice PK/PD data for an antibody drug at 2 and 8 mg/kg
> weekly i.p. for 4 weeks. The PK data showed dose proportionality and
> the PD effect reached saturation at these doses. After modeling using
> sigmoid Emax model, I got quite different EC50 for the two doses, 11
> ug/mL for the lower dose and 26 ug/mL for the higher dose.
>
> Could someone give me some insight on why the low dose gave me higher
> EC50 at saturation of response?
>
Two possible reasons:
1. Tolerance: At the higher dose you are getting de-sensitization and
therefore a higher EC50. How plausible this is will depend on your
specific drug and its effect. In the case of an antibody drug it might
be that a blocking antibody is formed to your drug.
2. Random Error: This is a more likely explanation. Because there is
error in your concentration and effect observations this will lead to
imprecise parameter estimates. If you fit the data from both doses
simultaneously you can force the Emax and EC50 to be the same for both
doses and see if this really makes the fit any worse compared with
fitting them separately.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Hello,
EC50 and Emax are properties of the drug. One should analyze data by
dose
groups. All available data should be analyzed to estimate one set of
parameters. You should strongly consider re-analyze both doses together.
Imagine the sigmoidal concentration-effect relationship, the lower
doses
will have effect (say) only till 40%, how can one estimate the Emax
(which
is say 100%)? You are bound have erroneous estimates.
Regards,
Joga Gobburu
Pharmacometrics
CDER, FDA.
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The following message was posted to: PharmPK
If you are reaching saturation at both of these doses, then it may be
unlikely that you can reliably estimate EC50. The best way to estimate
an EC50 is to have data near the 50% effect. Is there a sufficient
gradient of effect in your murine model to show effect building toward
the maximum? If not you may not have enough PD data to distinguish
between the two doses and any estimate of EC50 would be expected to be
highly correlated to dose.
Jeff
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