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Dear All,
Is there a method to estimate predose concentration? e.g. in a 2-period study,
the predose conc in period 2 is missing and I want to know whether the missing
conc is BLQ. Can I estimate the missing predose conc using information from the
period 1 by Winnonlin 5.2 ? How ?
thanks
John
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The following message was posted to: PharmPK
Dear John,
if you are bound to NCA for a regulatory submission you can calculate the pre-dose
concentration (given you have a reliable estimate of Lambda_z). In WinNonlin's
terminology:
C=Clast*exp(-Lambda_z*(t-Tlast)),
where C ist the calculated pre-dose concentration, t the time of the pre-dose
concentration in period 2 (where t=0 is the time point of administration in the _first_
period; if you have e.g. a washout of 1 week this value will be 168 hours), Lambda_z the
estimated elimination, and Clast the last measured concentration in period 1 (at Tlast).
Whether or not any agency would accept such a procedure: no idea.
Best regards,
Helmut
-
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.aaa.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at/
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The following message was posted to: PharmPK
Dear john,
If you have concentrations from period one, you can estimate the concentration
remaining at the predose time given the half life. If you don't have
concentrations from period 1 and it is oral administration, then i guess you
cannot estimate it. If IV, then you can estimate it using the first post-dose conc
and the ln(cp1/cp2)=kt equation (assuming one comp model)
Hope this helps
Ahmed Mohamed M.S.
Purdue University, Pharmacy Practice
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Dear Helmut,
Many thanks! Just want to learn. Is there any rational for this equation.
John
--
Hi Ahmed,
I have concentrations from period 1, iv administration. could you give me little bit
detail what is cp1 and cp2? how to get kt, by modeling?
Thanks
John
[You might have a look at http://www.boomer.org/c/p4/c04/c0401.html
and http://www.boomer.org/c/p4/c14/c1401.html
and the following pages - db]
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The following message was posted to: PharmPK
Dear John,
> [...] Just want to learn. Is there any rational for this equation.
We estimate the concentration based on the last observed in period 1 and
the elimination assuming a one-compartment model. Generally this
equation is used if we want to estimate the trough-concentration in
steady state at exactly tau when we have a time deviation from the
sampling schedule (let's say we planned for 24 hours and sampled 10
minutes later). The method is similar to extrapolating AUC from Tlast to
infinity (based on the last observed concentration). Reference:
Gabrielsson J and D Weiner
Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications
Swedish Pharmaceutical Press, Stockholm, p163 (4th ed. 2006)
Try it with Exp1.pwo from the WinNonlin's examples folder. You will get
Lambda_z 0.06463 (estimated from 12-24 hours). For a one-week washout we
may estimate the pre-dose in period 2 from 1.287*exp(-0.06463*(168-24))
as 0.0001168.
There is an alternative method (independent from Clast) but not so easy
to implement in WinNonlin:
C=exp(C0-Lambda_z*t)
I don't know which version of WinNonlin you are using; in 'classical'
WNL (up to v5.3), check 'Text' and 'Output intermediate calculations' in
the Model Options before running NCA. Then you get the
ln-transformed-intercept (C0) in the ASCII-output - unfortunately not in
any of the worksheets. From Exp1.pwo we will get an intercept of 1.7992.
Try the formula with t=12, 14, 24. You will get 2.783, 2.446, and 1.281
- actually WinNonlin's predicted values. For a one week washout (168 h)
we may estimate the pre-dose in period 2 as 0.0001163.
In Phoenix/WinNonlin check 'Intermediate Output', but again the
intercept is not given in a worksheet - only in the core output.
Best regards,
Helmut
-
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.at.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at/
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