Back to the Top
Is the effective half life different from terminal half life or biological half life? I have seen publications containing both terminal half life and effective half life of the same compound in the same paper. This tells me these two are different. Question is how the effective half life is calculated? This is not mentioned in the papers.
Thanks for your quick reply.
Regards,
Thomas Nadakal
Back to the Top
The following message was posted to: PharmPK
This topic has been covered extensively and also quite recently. I would
refer you to responses by Les Benet and his pragmatic publication which
discusses inter alia the use (and abuse) of effective half-life (Pharm Res
2008; 25(12):2869-2877).
Back to the Top
The following message was posted to: PharmPK
Hi,
Thomas Nadakal wrote:
> Is the effective half life different from terminal half life or biological half life? I have seen publications containing both terminal half life and effective half life of the same compound in the same paper. This tells me these two are different. Question is how the effective half life is calculated? This is not mentioned in the papers.
A half-life is often a convenenient parameter to describe an exponential process. First order biological processes can be described by rate constants that have equivalent half-lives. But this is usually not the case for the time course of drug effect.
If the time course of drug effect exactly follows the time course of an exponential model for drug concentration then they PK half life would describe the half-life of loss of drug effect. However, this is an unusual circumstance because it requires that the concentration-effect relationship is linear i.e. drug effects are linearly related to drug concentrations. In general all drugs have a non-linear relationship between concentration and effect. If drug concentrations are higher than about 25% of the EC50 (typically this will be an EC20 producing 20% of Emax) then the conc-effect relationship will be non-linear and there is no sensible meaning to the term 'effective half-life' as a parameter describing the time course of drug effect. A half-life only makes sense when the process being described has has an exponential time course.
People who describe drug effect time course with an 'effective half-life' are usually demonstrating they are ignorant about the principles of PK and PD.
Nick
-- Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
Back to the Top
The effective half life should be for radiopharmaceutical administered in body. It combines both, the physical decay half life and elimination half life of the radiopharmaceutical.
Nadeem Irfan Bukhari, PhD.
Back to the Top
Hi Nick,
Effective half life is also used independent of PD as the half life that reflects drug accumulation:
Boxenbaum & Battle 1995, Effective half-life in clinical pharmacology, J.Clin.Pharmacol, 35, 763
I believe this is an acceptable, non-ignorant and even valuable use of that term (the problem with terminal half-life is, that it may have very limited relevance for the disposition and accumulation of a drug).
best regards, Markus
H Markus Weiss, PhD
Novartis Institutes for BioMedical Research Translational Sciences - DMPK CHBS, WSJ-210.4.25
Novartis Pharma AG, Werk St. Johann
CH-4057 Basel, Switzerland
Back to the Top
Thanks for the answers posted on the question on effective half life. As a follow up, what is the use of knowing "effective half life" apart from knowing about drug accumulation, which I can find easily from ratio of AUC's of initial dose and the final dose? Can I use it to design a dosing schedule (rate) ? Has any body used this half life to design clinical dosing regimen? Is the effective half life calculation methods in the papers correct? I get different numbers when I follow Bennet's or Bauxenbaum's papers, unless I am making a silly mistake.
Thanks again for the previous answers from some great minds.
Thomasapy.at.yahoo.com
Back to the Top
Effective half-life is also useful in determining the most logical dosing interval
for chronically administered drug. It is totally inappropriate to determine dosing interval on the basis of terminal elimination phase half-life when that parameter represents only a fraction (eg., 1%) of total systemic drug exposure.
With regards,
Aziz Karim
Back to the Top
Markus,
Thanks for your further comments and for pointing out the paper by Boxenbaum & Battle which uses a term originally proposed by Kwan & Duggan (1977) at a time when pharmacokinetics was defined as describing the time course of both drug concentrations and drug effect (Benet 2008). However, at least since 1980 (see Benet 2008) the importance of distinguishing the time course of drug concentrations and drug effects has been central to modern clinical pharmacology.
I think that the use of the term 'effective' half-life to describe the time course of concentration is a misnomer which should therefore be avoided. As illustrated earlier in this thread, the use of the term "effective" without qualification can be easily confused with a half-life trying to describe the time course of effect. The use of this term today to describe a pharmacokinetic property reflects some ignorance about the meaning of the word "effect" in clinical pharmacology.
Sahin & Benet have more recently proposed an "operational half-life" and Eger & Shafer have described a "context sensitive decrement time" which along with the Kwan & Duggan/Boxenbaum & Battle "effective half-life" are similar in trying to describe a time course which depends on multiple processes with just one parameter. This is necessarily an approximation because it is impossible to define a multiple parameter system accurately with just one parameter. Boxenbaum & Battle acknowledged this as a weakness of the "effective half-life".
If I want to understand the time course of drug concentrations and drug effects then I use model based simulation e.g. to find out when the concentrations reach 90% of the predicted steady state or drug effects have fallen to 50% of the value when drug input stopped. Simulation is as accurate as the original model parameters and can be used to demonstrate graphically what is predicted to happen both for PK and PD. This is especially valuable in communicating with those who are not familiar with quantitative models. Simulation has been accepted for over a decade (Bonate 2000) as an important tool for understanding clinical pharmacology in drug development in order to make the best predictions for future clinical trials and clinical use of drugs.
Nick
1. Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J Clin Pharmacol. 1995 Aug;35(8):763-6.
2. Kwan KC, Duggan DE. Pharmacokinetics of Sulindac. Acta Rhumatol Belg. 1977 Jul-Dec;1(3-4):168-78.
3. Benet, LZ. http://www.cognigencorp.com/nonmem/current/2008-November/1225.html 2008
3. Sahin S, Benet LZ. The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms. Pharm Res. 2008 Dec;25(12):2869-77.
4. Eger EI, 2nd, Shafer SL. Tutorial: context-sensitive decrement times for inhaled anesthetics. Anesth Analg. 2005 Sep;101(3):688-96, table of contents.
5. Bonate PL. Clinical trial simulation in drug development. Pharm Res. 2000 Mar;17(3):252-6.
-- Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
Back to the Top
Nick,
thanks for bringing a historical and conceptual perspective into the discussion on the term "effective half life" which is interesting for me to appreciate!
I would like to make two further comments:
1) I believe that the original question from Thomas Nadakal was indeed relating to a use of the term "effective half life" as defined by Kwan and Boxenbaum (in a PK context, I think this is supported by his second question placed in this thread). To answer this question it is useful to refer to Boxenbaum.
2) While effective half life may get confused with an "effect half life" I don't think it is a misnomer and to me this confusion is not self-evident. The concept as described by Boxenbaum and Battle is also today useful and I would not hesitate to use this parameter, even though it has some limitations as you convincingly describe.
Best regards, Markus
H Markus Weiss, PhD
Novartis Institutes for BioMedical Research Translational Sciences - DMPK CHBS, WSJ-210.4.25
Novartis Pharma AG, Werk St. Johann
CH-4057 Basel, Switzerland
Back to the Top
The following message was posted to: PharmPK
This is a topic that has been discussed many times in this forum and so I would encourage individuals to consult the archives before posing questions because there is nothing new to say. I would however agree with Markus that there is nothing wrong with use of the term effective half-life.
regards
Brian
[Thanks Brian, 168 matches when entering 'effective half-life' on http://www.boomer.org/pkin/simple.html
- db]
Back to the Top
Dear PK scientists,
Thanks for the comments on effective half life. Davies is correct, this terminology was mentioned many times before, in this forum. That itself shows this is an interesting topic. The reference paper by Boxenbaum is also correct in certain aspect. But is this correct always? The equation, contains the term Keffective which is used to calculate the effective half life by using 0.693/t 1/2, if I understands correctly. Why suddenly switching to first order kinetics to calculate t 1/2. Is this the right way when we are dealing with multiple dosing cases and when we have tissue accumulation? Then we have the paper by Les Bennet where we came up on a different terminology for effective half life and different equation . Can we use the effective half life and predict a dosing interval correctly? Most probably not. We may be overestimating and get incorrect dosing interval.
Thanks again for the useful and interesting comments.
Thomas Nadakal
Back to the Top
The following message was posted to: PharmPK
Thomas Nadakal wrote:
> Can we use the effective half life and predict a dosing interval correctly? Most probably not.
Dosing intervals should be chosen based on the expected duration of effect, adverse effects and practical issues such as patient convenience. Dosing less often than once a day is rarely of any practical use so the issue about dosing interval is only important if the the duration of effect is not long enough for once a day dosing. The dosing interval is then chosen so that the duration of effect is long enough in the dosing interval while avoiding adverse effects from too large a dose. Note that this decision is not based on PK properties - it is based on the time course of effect (beneficial and adverse).
The mis-named 'effective' half-life does not relate to effect -- it relates to PK alone. It is therefore insufficient by itself to predict a sensible dosing interval.
Nick
Back to the Top
The equation for effective half-life calculation is straight forward, clearly related to the accumulation ratio. However, what would best explanation, if a drug's effective half-life is 2 to 3 times of terminal half-life? -- too small amount of terminal phase?
Lisa
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 "Effective half life" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)