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From: Gary Maier
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK Re: Effective half-life and multiple dosing
Date: Wed, 24 Nov 1999 07:53:18 -0500
Hello,
I have also seen effective half-life expressed as a function of accumulation
ratio for AUC0-tau for example at steady-state. Thus if the accumulation
ratio (R)for AUC0-tau is 2 an effective multiple dose t1/2 could be
estimated as:
beta= ln(R-1/R)/tau or 0.0288 (t1/2(eff) of 24 hours where tau=24 hours
Any comments on this approach would be appreciated.
Gary Maier
Sepracor
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Date: Wed, 24 Nov 1999 10:08:48 -0500
From: Sriram
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To: PharmPK.aaa.boomer.org
CC: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Re: Effective half-life?
Dear all
We had a situation recently when we used effective half-life.
We had to compare the terminal half-lives after two different doses of a drug
given by inhalation to see if they were different.
The assay limit was not sufficient to adequately characterize the
terminal phase
(bi phasic) for the low dose.
And since we had single and multiple dose data , we calculated accumulation by
AUCss/ AUCsingle dose and then the accumulation rate and then the effective
half-life. When we compared the eff half-lives of these two doses ,
they were not
significantly different whereas if we had used the terminal slopes for
comparison, we would have seen a difference between the doses.
In other words, effective half-life gave us a way around to compare two doses
even with assay limitations.
Sriram
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Date: Wed, 24 Nov 1999 07:36:55 -0800
From: "Dr. Michael Mayersohn"
Organization: College of Pharmacy
X-Sender: "Dr. Michael Mayersohn"
To: PharmPK.at.boomer.org
Subject: Re: PharmPK Re: Effective half-life?
Several of the previous definitions of "effective" half-life are
incorrect. Perhaps a better term is "accumulation" half-life, since it
represents the apparent value for half-life consistent with the extent
of drug accumulation following multiple dosing. The term was first used
by Kwan and is discussed in the Boxenbaum paper cited previously.
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Date: Wed, 24 Nov 1999 15:04:34 -0700
From: "David Nix, Pharm D."
Organization: College of Pharmacy
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Re: Effective half-life?
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elixir.Pharmacy.Arizona.EDU id PAA01165
There appears to be much confusion about terminology with "effective
half-life" Harold Boxenbaum's paper coined the term to account for
accumulation after multiple dosing.
The accumulation ratio =AUCss/AUCsd (ss=steady state; sd=single dose
or first dose). This ratio is set equal to 1/(1-exp(-ln(2)/t1/2eff)).
One then solves for the effective half-life (t1/2eff). With multiple
compartment models, the terminal half-life provides very poor
information about the expected accumulation on multiple dosing and when
a "practical steady-state" would be reached. To be exact steady-state
would be reached only after 5-7 times the terminal half-life. However,
in many cases a terminal half-life and amount of drug associated with
the deep compartment contributes little to the overall accumulation and
total area. For this reason, I find the "effective half-life to be
sometimes more useful than a "terminal half-life".
The apparent half-life was also used in some of the discussions.
Half-life should only be discussed when the pharmacokientics are linear
(first order). Usually, this term is associated with the terminal
half-life (ie. ln(2)/apparent terminal elimination rate constant). The
word "apparent" is included because we are never sure if the "terminal
half-life" can be determined with the data. The terminal half life will
often get longer if one samples for a longer period of time or if a more
sensitive assay is used.
Brain Davies pointed out that the product of ln(2) x MRTiv also has
been termed the effective half-life. This term is discussed in Gibaldi
and Perrier text "Pharmacokinetics" 2nd ed 1982. However, I am not sure
if this was previously defined and published in primary literature.
Perhaps it would be less ambiguous to use t1/2acc (accumulation
half-life) and t1/2mrt (effective half-life determined from MRT). In
addition it may be useful to describe the relationship between t1/2acc
and t1/2mrt.
David Nix
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