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Should (or can) the 'half-life' (interpreted by many potential readers to mean elimination
half-life) be calculated using NCA if data points towards the end of sampling times
(including Clast) reproducibly tend to plateau due to re-distribution of low
concentrations of drug from tissues back into peripheral compartments. Put slightly
differently, for a drug with a long half-life (eg 1 week) is it ever reasonable to
'accept' under experimental conditions, a true elimination phase may never be identified
so either instead focus on a distribution half-life or instead don't actually focus on
half-life at all ? I've seen instances where WinNonLin has produced a half-life value but
I don't believe it's necessarily appropriate but wonder if others have come across a
similar issue. I do not have experience in compartmental modelling so am unaware if this
assists with such estimations.
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Dear Keith,
The half life estimated using NCA (NCA half-life) informs you about the
time required for reducing the concentrations in plasma to its half.
This is valid for the phase where you have taken the points for lambda
estimation.
The relationship between this NCA half-life and the elimination process
will depend on the PK profile of the drug. If the drug follows a
mono-exponential profile the NCA half life will be representative of the
elimination process, but for bi-exponential and tri-exponential profiles
the NCA half-life will combine information about elimination and
distribution processes. Consequently, in bi-exponential and
tri-exponential profiles the NCA half-life describes how the drug
disappears from the plasma, but not its elimination process. The
compartmental model will allow you to distinguish between distribution
and elimination.
Ignacio Ortega
Pharmacokinetics and Drug Metabolism Area
Research, Development and Innovation Department
FAES FARMA
Maximo Aguirre 14. 48940 Leioa
Spain
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Keith: It seems to me that what you are considering is achieving the
terminal elimination phase (NCA). Therefore ideally blood sampling
should be continued to investigate characterizing the terminal
elimination phase. In doing so one can then focus on this elimination
and measure the rate of elimination and hence the AUC to inf and
half-life. Should this not be the first step to best characterize the
drug pharmacokinetics?
WinNonlin will produce values for half-lives that are not correct if the
terminal phase has not been achieved from the sampling schedule.
For drugs with very long half-lives it may not be practical routinely to
have the sampling schedule you would like. So I wonder if limited
sampling plus compartmental modeling (if needed) could be useful in
describing the extended drug pharmacokinetics. {The focus would be on
AUC to time point t as the measure of exposure and not so much on half
life or AUC to inf}
Hope comments help,
Angus McLean
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The following message was posted to: PharmPK
Hi Keith,
The half-life determined using NCA from the later sampling times should
be
defined as "apparent terminal half-life". Unless conforming to a
one-compartment disposition model, elimination half-life can only be
reliably derived from a compartment model, preferably with data after
single
and multiple dosing (previously discussed on this site).
By the way, a prolonged terminal half-life may be due to re-distribution
from a peripheral (deep) space (e.g. fat, bone) into the central
(sampling)
space.
For a drug with a half-life of 1 week, a sampling period of at least 3
weeks
is required and an assay with sufficient sensitivity to measure drug
over
that entire period. If this is not possible, you can get at least an
idea of
the true elimination half-life using the "effective" half-life based on
extent of accumulation in plasma (as discussed previously on this site);
7.
Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J
Clin. Pharmacol.. 1995; 35: 763-766
Charlie
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Keith,
In general, when people report half life, it is the half life of the terminal
phase (0.693/lambda). You have to be careful with the interpretation of this value as it
describes the half life of the terminal phase only regardless of how much this phase
contributes to the overall PK profile of the drug. For example, if a prolonged
(days-months) flat terminal phase starts when drug concentration already falls to 1% of
its C0 during the initial phase(s), we can't say the half life of this drug is days or
months. In that case the half life of the initial phase (s) are definitely more relevant
than the terminal half life.
To account for the differences in the contributions of the different phases to the
overall PK profile, an effective half life can be calculated as (i) mean residence time *
0.693 or (ii) the sum of the half life of every phase multiplied by the %AUC of every
phase/Overall AUC.
Yazen Alnouti
University of Nebraska Medical Center
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Dear Alnouti,
I had an extended question for the terminal half life. Drug accumulation and the time to
reach steady state are calculated in textbooks by using terminal half-life, but the
equations are derived based on the drug disposition is mono-exponential. While most drugs
display multi-phasic disposition, I fail to find calculations of the accumulation and the
time to reach steady state, for the drug with multi-exponential PK profile. How clinically
do we deal with this? Can the " effective half life " be used instead of terminal
half-life?
I appreciate anyone's opinion.
Ralf
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The following message was posted to: PharmPK
You are correct in what you say - calculations in text books use a
mono-exponential system and so are approximations for a
multi-compartmental system. For a multi-compartmental system the time to
steady state needs to be an iterative process. One way to do this is to
use the effective half-life. The effective half-life suggested by Harold
Boxenbaum is calculated from the accumulation factor. If you have this
it is a simple calculation. If you need to calculate the accumulation
factor, the equation given by Harold is based on a mono-exponential
model. If you have an IV drug then it is simple to calculate an
effective half-life from 0.693 x MRT. Unless you are prepared to use a
modeling approach there is no simple way to calculate time to steady
state using NCA.
Hope this helps
Regards
brian
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Yes Ralf, there is a half-life effective/functional, of which the most
useful application is to calculate accumulation in multiple dosing. See
Clin Drug Investig. 2006;26(12):681-90.
Functional half-life is a meaningful descriptor of steady-state
pharmacokinetics of an extended-release formulation of a rapidly cleared
drug : as shown by once-daily divalproex-ER.
Dutta S, Reed RC.
J Clin Pharmacol. 1995 Aug;35(8):763-6.
Effective half-life in clinical pharmacology.
Boxenbaum H, Battle M.
Anesthesiology. 1992 Mar;76(3):334-41.
Context-sensitive half-time in multicompartment pharmacokinetic models
for intravenous anesthetic drugs.
Hughes MA, Glass PS, Jacobs JR.
J Pharmacokinet Pharmacodyn. 2011 Jun;38(3):369-83. Epub 2011 Apr 16.
Intermittent drug dosing intervals guided by the operational multiple
dosing half lives for predictable plasma accumulation and fluctuation.
Grover A, Benet LZ.
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