- On 22 Nov 1999 at 22:47:59, (GCA02464.-at-.nifty.ne.jp) sent the message

Back to the Top

Dear all,

Many papers on pharmacokinetics of ACE inhibitors describe

"effective half-lives".For example:

benazepril (Am-J-Vet-Res.1995,56:1620-8 &

Biopharm-Drug-Dispos.1989,10:365-76)

cilazapril (Eur-J-Drug-Metab-Pharmacokinet.1990,15:63-7)

lisinopril (Biopharm-Drug-Dispos.1989,10:397-409 &

Eur-J-Clin-Pharmacol.1988,34: 61-5)

enalapril (Biopharm-Drug-Dispos.1984,5: 273-80).

Does anyone know what the "effective half-life" means?

Does it reflect drug elimination?

Masaki Hiraoka - On 23 Nov 1999 at 11:10:26, Kazimierz Kozlowski (khkoz.-at-.czd.waw.pl) sent the message

Back to the Top

From: Kazimierz H. Kozlowski, Pharm. D.

Laboratory of Pharmacokinetics

The Children's Memorial Health Institute

04-736 Warsaw, Poland

e-mail: khkoz.-at-.czd.waw.pl

Dear Dr Hiraoka,

Effective half-life is discussed in the article: Boxenbaum H. et al.:

Effective half-life

in clinical pharmacology. J. Clin. Pharmacol. 35(8), 736-6, 1995.

This pharmacokinetic phenomenon is reflect underestimation of terminal

half-life after single dose.

Mechanism is distributional or protein binding.

Sincerely

Kazimierz H. Kozlowski - On 23 Nov 1999 at 20:00:47, David_Bourne (david.-a-.boomer.org) sent the message

Back to the Top

[A few replies - db]

=46rom: Thomas.Senderovitz.at.ferring.com

To: PharmPK.at.boomer.org

Subject: RE: PharmPK Effective half-life

Date: Tue, 23 Nov 1999 08:48:32 +0100

Dear Masaki Hiraoka,

The so-called "effective half-life" is not a very good term to use.=20

It is used for two-compartment models to describe one half-life for=20

the drug. This is not very precise, since such drugs have actually=20

two half-lives - one for each exponential phase, and to put them into=20

one will actually not describe the elimination accurately. I prefere=20

to use both of them instead (t=BD-lambda 1 and t=BD tambda 2) - and be=20

careful not to draw the conclusion that the lambda2-halflife=20

(previously called the beta half-life) is the elimination half-life,=20

as elimination may occur during the lambda-1 phase as well.

Regards

Thomas Senderovitz, MD

Associate Head of Clinical Pharmacology

Product Development, Clinical Research

Address:

=46erring Pharmaceuticals A/S

=46erring International Center

Borups All=E9 177

DK-2400 Copenhagen NV

Denmark

Phone:

Direct: +45 38 15 04 58

Switchboard: +45 38 15 03 00

Mobile: +45 24 25 52 24

=46ax: +45 38 15 04 58

E-mail address: Thomas.senderovitz.at.ferring.com

---

Date: Tue, 23 Nov 1999 02:47:02 -0700 (MST)

X-Sender: ml11439.-at-.pop.goodnet.com

To: PharmPK.-at-.boomer.org

=46rom: ml11439.-at-.goodnet.com (Michael J. Leibold)

Subject: Re: PharmPK Effective half-life

Hello Masaki,

In my experience the "effective half-life" refers to the "apparent

half-life" of a drug given the realities of multicompartment kinetics.

That is, gentamicin and vancomycin are dosed based on their effective

half-lives, which are derived from one-compartment kinetic analysis of

serum levels. However, these are "effective half-lives" since their

pharmacokinetics are actually multicompartment.

The half-life measured for gentamicin does not actually represent

the terminal elimination phase since the beta phase is followed by a

much longer washout phase reflecting the slow release of gentamicin

from renal tissue. Nevertheless, the T1/2beta measured for gentamicin

can be used to effectively dose the drug, since the T1/2gamma only

results in slow accumulation over a longer period of time.

Generally, the "effective half-life" represents the half-life of

the terminal elimination phase, except in the case of drugs which

accumulate in the tissues (like gentamicin). In the later case, the

"effective half-life" represents the half life of the principal

elimination phase, distinct from the deep tissue accumulation phase.

The half-life of the deep tissue accumulation phase reflects a much

slower deep tissue binding process not concerned with elimination of

the drug from the body.

So, the "effective half-life" is the half-life which is used in

the following equations to determine one compartment pharmacokinetic

constants:

One compartment pharmacokinetic model:

Cp2=3D (Cp1)e-Ket

ln Cp2- ln Cp1=3D -ket

1) Ke=3D [ln Cp1- ln Cp2]/[time]

If the ratio of Cp1/Cp2 equals two, then ln Cp1/Cp2=3D 0.693, and the

[time] in the denominator of equation becomes the half-life, since it

represents the time it takes for the Cp1 to decrease to 1/2 of Cp1.

2) Ke=3D 0.693/T1/2

3) T1/2=3D .693/Ke

4) T1/2=3D 0.693(Vd)/Cl

5) Cl=3D 0.693(Vd)/(T1/2)=3D KeVd

In effect, these equations can used to dose most drugs which exhibit

linear pharmacokinetics. In reality however, virtually all drugs obey

multicompartment pharmacokinetics. As a result, the T1/2 of a drug is

frequently referred to as the apparent half-life, or the effective half-life=

=2E

I have even read a paper on phenytoin phramacokinetics in which the author

assumed a one compartment linear pharmacokinetic model to determine the

apparent T1/2 for phenytoin. Although phenytoin obeys nonlinear kinetics,

the author was able to dose several patients using the apparent half-life

of phenytoin in each patient.

In short, the "effective half-life" refers to the assumption of one

compartment pharmacokinetics for drugs which actually obey more complicated

pharmacokinetic models. That is, the term "effective" half-life reflects

that it is a simplification of a more complex pharmacokinetic process.

Mike Leibold, PharmD, RPh

ML11439.aaa.goodnet.com

---

Date: Tue, 23 Nov 1999 08:05:49 -0500

=46rom: Sriram

X-Accept-Language: en

To: PharmPK.at.boomer.org

CC: Multiple recipients of PharmPK - Sent by

Subject: Re: PharmPK Effective half-life

Here is a reference for your question

Harold Boxenbaum and Michele Battle, J Clin Pharmacol 1995; 35: 763-766

---

=46rom: "Brian E. Davies"

To:

Subject: Re: PharmPK Effective half-life

Date: Tue, 23 Nov 1999 10:08:27 -0500

X-Priority: 3

My own definition of effective half-life would be derived from the MRT as

follows:

CL =3D Vss x kss

kss =3D 1/MRT

Effective half-life =3D 0.693 / kss

=3D 0.693 x MRT

see also the paper by Harold Boxenbaum which uses the accumulation factor in

the calculation of effective half-life.

The effective half-life is used for a multicompartment drug and is

particularly useful when the contribution of the first phase is considerably

greater than that of the terminal phase i.e. elimination is faster than

distribution. In this case the terminal rate constant will approximate k21

and will not reflect the elimination of the drug. A good example of a drug

of this type is gentamycin. Over 98% of an intravenous dose is eliminated

before distribution equilibrium with all tissues of the body has been

achieved. Using f1 and f2 to denote the fraction of elimination associated

with the 2 exponential terms of a 2-compartment model, for gentamycin f2 is

close to 0 and so it is the half-life of the first phase that primarily

determines the elimination and the time to reach plateau. The effective

half-life is a reflection of the relative contributions of the 2 phases and

is the ideal solution to the question: "what is the half-life" and can be

used for estimating time to plateau and dosing intervals for those drugs

that need to be dosed in multiples of the half-life.

Brian Davies

Advanced Biomedical Research, Inc.

brian.davies.at.abr-pharma.com - On 25 Nov 1999 at 10:59:32, David_Bourne (david.at.boomer.org) sent the message

Back to the Top

Date: Thu, 25 Nov 1999 19:34:33 +0900

From:

To: PharmPK.at.boomer.org

Subject: Re: Effective half-life

Many thanks to Kazimierz, Thomas, Mike, Brian, Sriram, Gary,

Michael, David and all of you.

Following is my understanding:

"Effective half-life" is calculated from accumulation factor

of the drug with apparent multiple compartment model. So it

is better called as "accumulation half-life."

Accumulation factors are usually calculated from the ratios

of AUC(tau, at SS)/AUC(tau, single), Cave(SS)/Cave(single),

Cmin(SS)/Cmin(single) etc.

For a drug whose trough is in terminal elimination phase, the

trough values at SS may reflect accumulation factor from

Cmin(SS)/Cmin(single), and "effective half-life" may be close

to terminal elimination half-life. And in the case accumulation

occurs in first order, increase in AUC(tau) can be interpreted

"effective half-life" from AUC(tau, at SS)/AUC(tau, single).

This is useful when terminal half-life is not precisely

obtained or is not a dominant factor for accumulation.

But I think there may be several factors that cause increase

in AUC(tau), Cave or Cmin after repeated administration.

Some may not relate to elimination of drugs.

Thus, consideration on the factors affecting accumulation

factor is necessary for each specific case to use "effective

half-life".

How does my understanding sound?

Any comments are welcome.

Masaki Hiraoka

---

Date: Thu, 25 Nov 1999 09:31:06 -0500

From: "Oo, Charles {CLIN~Nutley}"

Subject: RE: PharmPK Re: Effective half-life and multiple dosing

To: "'PharmPK.aaa.boomer.org'"

Dear all,

Would like to expand on what is being discussed.

Effective or accumulative half-life is a practical concept in

assessing drug accumulation ratio, steady-state Cmax, Cmin and

fluctuation during multiple dosing of a multi-compartmental drug.

The half-life (or rate constant k) that affects drug accumulation is

the one that is just prior to a particular dosing interval tau. The

general equation is:

Accumulation ratio = (1)/(1-EXP(-k* Tau))

This effective or accumulative half-life is contingent upon the

dosing interval (tau) used. This is the half-life that will

determine accumulation with the respective dosing interval. This is

the half-life that is meaningful to multiple dose therapy and

steady-state simulation from single dose data.

The deeper compartmental half-life may be just an academic curiosity.

It has been said that with the advent of more sensitive bioanalytical

techniques, the terminal half-life of drugs get longer. The deep

compartment half-life may not mean anything if the dosing interval

(tau) used in therapy is shorter.

Also, I think we should stop using the word 'apparent' before

half-life because all half-lives are apparent.

Comments would be appreciated.

Charles Oo Pharm.D., Ph.D.

Hoffmann-La Roche Inc.

Clinical Pharmacology

Building 1/3C27

Nutley, NJ 07110-1199

Tel: 973-562-2575

Fax: 973-235-5635 - On 26 Nov 1999 at 10:44:18, David_Bourne (david.-a-.boomer.org) sent the message

Back to the Top

[A few replies - db]

From: "Hans Proost"

Organization: Pharmacy Dept Groningen University

To: PharmPK.-at-.boomer.org

Date: Fri, 26 Nov 1999 09:07:22 MET

Subject: Re: PharmPK Re: Effective half-life

X-Confirm-Reading-To: "Hans Proost"

X-pmrqc: 1

Priority: normal

With respect to 'effective half-life', Masaki Hiraoka wrote:

> This is useful when terminal half-life is not precisely

> obtained or is not a dominant factor for accumulation.

To my understanding, the longest (=terminal) half-life is always the

dominant factor for accumulation. Are there any circumstances

where the accumulation is not governed by the longest half-life.

Of course, if the terminal half-life is associated with a very small

intercept, it may not become apparent in the accumulation factor

observed from plasma concentration profile. But the accumulation

in the 'deepest' compartment is certainly governed by / associate

with this terminal half-life.

> But I think there may be several factors that cause increase

> in AUC(tau), Cave or Cmin after repeated administration.

> Some may not relate to elimination of drugs.

This is a rather cryptic phrase, and in my opinion not correct.

Accumulation, in terms of AUC(tau) and C_average is governed by

clearance only, and not by distribution.

Of course, the half-lives are related to clearance, and so it may be

said that the accumulation is related to the half-lives, but this is a

rather confusing and 'dangerous' way of reasoning.

Best regards,

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.aaa.farm.rug.nl

---

Reply-To: "Stephen Duffull"

From: "Stephen Duffull"

To:

Subject: Re: PharmPK Re: Effective half-life

Date: Fri, 26 Nov 1999 09:01:29 -0000

Organization: University of Manchester

X-Priority: 3

Re discussion on half-life

If I remember correctly there was considerable discussion

about half-life on this discussion group around September

this year, when I believe much of the current topic and

related areas were battled out in the time honoured manner.

Is there a repository available for those who may have

missed this lively discussion?

[Yes there is...I have put the discussions on-line with annual

indexes on the page http://www.boomer.org/pkin/ - db]

Regards

Steve

=====================

Stephen Duffull

School of Pharmacy

University of Manchester

Manchester, M13 9PL, UK

Ph +44 161 275 2355

Fax +44 161 275 2396

---

X-Sender: klotx.-a-.mlucom6.urz.uni-halle.de

Date: Fri, 26 Nov 1999 11:41:31 +0100

To: PharmPK.at.boomer.org

From: "Prof. Michael Weiss"

Subject: Re: PharmPK Re: Effective half-life

In linear pharmacokinetics the only general valid concept (independent of

specific compartmental models or number of exponentials) is to deal with

accumulation and/or washout in terms of mean disposition residence time

(MDRT or MRTiv).

The accumulation ratio is RA = MDRT/T (T = dosage interval) and more than

90% of the plateau value (steady state) are reached in 3.7 MDRT (t90% < or

= 3.7 MDRT). After a single bolus dose more than 90% of the dose is

eliminated after 3.7 MDRT.

For more information, see: Weiss, M. The relevance of residence time theory

to pharmacokinetics. Eur. J. Clin. Pharmacol. 43: 571-579 (1992) and

references therein.

Michael Weiss

--------

Michael Weiss

Martin Luther Univ.

Dep of Pharmacology

Section of Pharmacokinetics

06097 Halle/Saale

Germany

Fax: 49-345-557 1657

Tel: 49-345-557 1835

michael.weiss.-a-.medizin.uni-halle.de - On 26 Nov 1999 at 14:49:53, "Gabriel Robbie 301-594-5305 FAX 301-480-3212" (ROBBIEG.aaa.cder.fda.gov) sent the message

Back to the Top

PharmPK discussion group:

We recently presented some of our work regarding the dependence of

effective half-life values on the method used for estimation at the

recently concluded AAPS 1999 meeting at New Orleans (Abstract # 1047). I

have attached the abstract at the end of the present message for your

convenience.

During our poster presentation at AAPS, the question most frequently

asked was,

1. Does effective half-life represent the half-life associated with

pharmacodynamic response (effect)?

Effective half-life does not relate to pharmacodynamics or effect. It is

a simplified half-life which when used in conjunction with the dosing

interval can predict the accumulation index of plasma/blood

concentrations at steady-state compared to the first dose.

Example: Let us consider a hypothetical compound, Drug X, which exhibits

multi exponential decline in plasma concentrations with a alpha, beta,

gamma and delta half-life (hours) of 1, 10, 75 and 150, respectively,

following oral administration. Let us also suppose that the drug is

administered once daily. The half-life which would help us in predicting

accumulation would obviously be the half-life associated with the major

phase (in terms of contribution to the total AUC). Similarly, the extent

of accumulation as reflected by the accumulation index (Rac) would shed

some light on identification of the major phase. If for the above

example, the Rac (ratio of the AUC in a dosing interval at steady state

to the first dosing interval) is approximately 4 to 5, then we know that

the major phase is the gamma phase or if the Rac is close to 9 then we

know the terminal phase is the major phase. Likewise, observed

accumulation (major phase concept) is used to calculate a hybrid

half-life, the effective half-life (Teff). The Teff concept might be

more readily understood when asked as a question, "No matter how many

half-lifes are associated with Drug X, if Drug X were to behave as one

with mono exponential characteristics what half-life would explain the

observed accumulation?"

To this end, the equation used for calculating accumulation index for

drugs with mono exponential characteristics is employed to estimate

Teff. The equation is Rac = (1)/[1-exp{-(0.693/Teff)tau}].

Researchers have used various methods such as, Cmax,ss/Cmax,1;

Cmin,ss/Cmin,1; AUCss/AUC0-tau; AUC0-inf/AUC0-tau and Css,ave/Cave,1

(same as AUCss/AUC0-tau). As was presented by us at AAPS, the Teff

values estimated from the ratio of trough concentrations at steady state

to trough concentration after the first dose (Cmin,ss/Cmin,1) might

result in overestimation of Teff. This is because the ratio of

Cmin,ss/Cmin,1 might reflect the terminal half-life and not Teff in

certain instances (high fluctuation between Cmax and Cmin - which is

dependent on dosing interval).

I hope this information helps.

Regards,

Gabriel Robbie, Ph.D.

Office of Clinical Pharmacology and Biopharmaceutics

CDER, FDA

ABSTRACT

Dependence of Effective Half-life on Estimation Method

G. J. Robbie and P. J. Marroum

Purpose: To evaluate the parameter dependence of accumulation index and

effective half-life and to identify an optimal pharmacokinetic parameter

for estimation of effective half-life.

Methods: Simulations of plasma concentrations were performed based on a

two-compartment open model with first order absorption. A fixed dosing

interval of 24 h, terminal half-life (T1/2,z) of 31.6 h and a terminal

area contribution of 30% to the total AUC were assumed. The Teff

estimated from three different ratios, Cmax,ss:Cmax,1,

AUC0-t,ss:AUC0-t,1, and Cmin,ss:Cmin,1 were compared. The effect of a

change in rate of absorption (Ka), absorption lag-time (Tlag), volume of

distribution (Vd) and elimination (K10) on Teff were evaluated.

Further, a sensitivity analysis was performed using Monte Carlo

simulations to assess the impact of variability (20-50%) in

pharmacokinetic parameter on Teff.

Results: The steady-state to single dose ratios of Cmax, AUC and Cmin

yielded Teff values of 8.2, 10.7 and 23.8 h, respectively. The Teff

estimated from the Cmin ratio was very different from Teff estimated

from the ratios of AUC and Cmax. Changes in Ka, Tlag and K10 had a

significant impact on Teff under certain conditions. A decrease in the

ratio of Ka:K10 (< 2) or an increase in Tlag resulted in a reduction in

the differences in Teff values estimated from the three ratios. The

results of the sensitivity analysis indicated that variability in

elimination would have a greater impact on Teff compared to variability

in absorption. The range of Teff values obtained based on AUC ratios for

high variability (50%) in K10 and Ka were 5.5 to 38.9 h and, 8.7 to 14.5

h, respectively.

Conclusions: Teff values are dependent on the parameter used for

estimation. At higher Ka:K10 ratios, the ratio of Cmin,ss:Cmin,1

overestimated Teff. Variability in elimination affects Teff to a larger

extent compared to absorption. The ratio of AUC0-t,ss:AUC0-t,1 is a more

reliable and robust method for estimation of Teff. However, the choice

of the estimation method used should also be based on clinical

considerations.

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

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)