- On 13 Feb 1998 at 11:41:34, "Dr.Robert E. Ariano" (rariano.aaa.mail.sbgh.mb.ca) sent the message

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In a post-graduate pharmacokinetic course, we have taught that plasma

half-life is not a normally distributed parameter. Texts such as

Goodman & Gilman, however, report plasma t1/2 for various drugs, as well

as, +/- some value (suggesting they have just reported the mean & SD

result of all t1/2's identified). The concern with this type of

reporting is the

that when we use this mean result as our priors (converted to a ke), for

such PK programs as USCPAK, we essentially overestimate the average

half-life for a drug within a population. Would anyone know by chance

who published this observation originally?

Regards,

Robert Ariano, PharmD, BCPS

Department of Pharmacy,

St.Boniface General Hospital,

Winnipeg, MB, Canada - On 16 Feb 1998 at 13:00:39, David_Bourne (david.aaa.pharm.cpb.uokhsc.edu) sent the message

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[db - a few replies]

Mime-Version: 1.0

Date: Fri, 13 Feb 1998 14:28:11 -0600

To: PharmPK.-at-.pharm.cpb.uokhsc.edu,

Multiple recipients of PharmPK - Sent by

From: "Hugh A. Semple"

Subject: Re: PharmPK Half-life of drug elimination

I think the following paper is where I first saw this topic discussed:

Lam FC, Hung CT, Perrier DG. Estimation of variance for harmonic mean

half-lives. J. Pharm. Sci. 1985; 74 (2):229-231.

Hope this helps.

Hugh

Hugh A. Semple, D.V.M., Ph.D.

Associate Professor of Pharmacy

College of Pharmacy & Nutrition

University of Saskatchewan

110 Science Place

Saskatoon, Saskatchewan

CANADA S7N 5C9

Phone (306)966-6365

FAX (306) 966-6377

"To me, the forest was peace and loneliness and freedom to think

and feel as I pleased. It was tangible nobility and it struck into my being

without literary interference. Later in life,when I was far from the

forest, I found the same thing in music."

Robertson Davies, from "The Cunning Man", 1994

---

From: "Thomas Senderovitz"

To:

Subject: Sv: PharmPK Half-life of drug elimination

Date: Fri, 11 Jul 1997 23:52:37 +0200

MIME-Version: 1.0

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Hello,

First of all i would like to state that reporting a mean +/- a value, which

could be a SD or SEM is not a good idea. IF a parameter is normally

distributed, the mean +/- 2SD would be more appropriate.

Then the next question. I do not think anyone can state that this and this

parameter is NEVER normally distributed. It really depends of the sample

size. Many of the PK parameteres you find in i.e. G&G are from rather SMALL

populations (and some of these "populations" are in fact healthy

volunteers). Under these circumstances you could argue that using

nonmarapetric statistics to describe your data is more correct ( such as

median and range). In reallity, in practical lift, I do not really think

this makes such a big difference, but as far as i know, no really good

trials have ever investigated the clinical consequences of using parametric

statistics instead of nonparametric statistical methods. I would rather

rocus on the PK values themselves - are they really POPULATION values?

Often the answer is no.

I hope these remarks are of some value!

Thomas Senderovitz, MD.

Clinical Pharmacology Unit

Bispebjerg Hospital

University of Copenhagen

E-mail: senderovitz.at.dadlnet.dk

---

Date: Mon, 16 Feb 1998 10:15:51 -0500

From: "Dr. William Webster"

Subject: Re: PharmPK Half-life of drug elimination

To: PharmPK.aaa.pharm.cpb.uokhsc.edu

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Construct a data set with ke's from say 0.1 to 0.00001 & then calc ulate

corresponding half-lives (Use spread sheet). Average each collum & see

that (ln(2)/ mean of the ke does not equal mean of the half life.

However, half-life may have normal distribution of error if the studies

averaged each subject's half life & did not predict average half life from

average ke.

The best model will have the ke parameter as a variable and not t1/2. Why

not do a comparison study of two different methods with the same data set.

The bottom line is how you apply results -- The more the data points, the

less the weight of the priors.\

Hope this helps.

W. Webster, Pharm.D., BCPS - On 17 Feb 1998 at 12:18:58, "Weber, Willi, HMR/DE" (Willi.Weber.at.hmrag.com) sent the message

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"reporting a mean +/- a value, which could be a SD or SEM "

does not necessarily describe a normal distribution. It is simply the

1st (mean) and 2nd moment (variability) of the unknown distribution,

which may further be characterized by the 3rd (skewness) and 4th

(kurtosis) moments. If the results for skewness and kurtosis do not

contradict the assumption of a normal distribution you may accept the

assumption of a normal distribution. In this case, the 95 % confidence

interval is given as mean +- 2 SD.

This topic is discussed in detail by:

William H. Press et al., Numerical recipes in C, 1988, Cambridge

University Press, p 472-475

regards

Willi - On 18 Feb 1998 at 11:27:00, Brad Bell (brad.-a-.apl.washington.edu) sent the message

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Would someone please post an exact mathematical definition of

what is meant by half-life in the message below. I am not sure if it has to

do with the error in parameter estimation or with mean residence time. - On 18 Feb 1998 at 11:27:49, Roger Jelliffe (jelliffe.-a-.hsc.usc.edu) sent the message

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Dear Drs. Semple and Senderovitz:

About using means + SD's, etc, for PK parameter values. In my

experience

many PK parameter distributions are significantly skewed to the right. This

is why it has been common for people to use lognormal distributions for

parameters. In addition, two or more subpopulations may be invloved, such

as fast and slow metabolizers of a drug.

One of the strengths of the nonparametric method of population

modeling is

that it makes absolutely no assumptioms about the shape of the distribution

of any of the parameters. Frequently the mean is significantly higher than

the median, and sometimes is close to the 75th percentile. Warren Dodge

examined this question in newborns receiving gentamicin, and found that

when mean pk parameter values were used, the resulting serum levels were

usually higher than predicted. When median valued were used, the measured

levels were better centered about the predicteions (Drug Invest 5: 206-211,

1993.

The real problem is how to develop dosage regimens that achieve target

goals most precisely. The problem with any method that obtains a single

best estimator of the parameter values is that there is only one version of

the patient, and that the dosage regimen computed to achieve the desired

target goal is assumed to achieve it exactly. There is no way to examine

the probability of missing the goal, or by how much.

Oe of the strengths of the nonparametric population models is that they

provide a discrete joint density ( a collection of discrete support points,

approximately one for each patient studied in making the original

population model. Instead of summarizing everything to get a mean or

median, for example, the collection of support points in the pop model,

when used as the Bayesian prior for developing the initial regimen, can be

used. Each support point provides a collectioon of parameter estimates

which can be used to predict subsequent levels regulting from a candidate

dosage regimen. The method can also detect unsuspected subpopulations

without further aid from other descriptors of covariates.

At the time a target goal is desired, one can compute, for each support

point, what the predicted error is in the achievement of the goal. Since

each support point also has its own estimated probability, one can now

compute the expected weighted squared error with which that particular

regimen fails to achieve the goal. One can then examine other regimens

until the one is found which specifically minimizes the expected weighted

squared error with which the goal is achieved.

This new "multiple model" method is a more precise method of hitting a

target goal than any single point set of parameter values, as it is

specifically designed to minimize the error with which the target goal is

achieved. This has been described by Bayard, Milman, and Schumitzky in Int.

J. Biomed Comput. 36: 103-115, 1994, by Taright, Mentre, Mallet, et al in

Therap. Drug. Monit. 16: 258-69, 1994, and more recently by Jelliffe,

Schumitzky, Bayard, et al in Clin. Pharmacokinet. 34; 57-77, 1998. Our

group is in the process of implementing a clinical software package based

on this new method.

The bottom line is that we want to be able to hit a desired target goal

with the greatest possible precision. Nonparametric population models

provide the structure for this, coupled with using the multiple model

method of developing dosage regimens. That has been our primary motivation

for using nonparametric population models.

Very best regards,

Roger Jelliffe

************************************************

Roger W. Jelliffe, M.D.

USC Lab of Applied Pharmacokinetics

CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033

Phone (213)342-1300, Fax (213)342-1302

email=jelliffe.at.hsc.usc.edu

************************************************

Take a look at our Web page for announcements of

new software and upcoming workshops and events!!

It is http://www.usc.edu/hsc/lab_apk/

************************************************ - On 20 Feb 1998 at 10:32:17, David_Bourne (david.at.pharm.cpb.uokhsc.edu) sent the message

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[two replies - db]

Date: Thu, 19 Feb 1998 14:08:29 -0800

From: "Dr.Robert E. Ariano"

Reply-To: rariano.aaa.mail.sbgh.mb.ca

Organization: St.Boniface General Hospital, Department of Pharmacy

Mime-Version: 1.0

To: PharmPK.-at-.pharm.cpb.uokhsc.edu

Subject: Re: PharmPK Re: Half-life of drug elimination

Hi Brad:

In response to your request for a definition:

"Half-life expresses the period of time required for the amount or

concentration of a drug to decrease by one-half".

Rob Ariano, PharmD, BCPS

Department of Pharmacy,

St.Boniface General Hospital,

Winnipeg, MB, Canada

---

From: Hans Proost

Organization: Pharmacy Dept Groningen University

To: PharmPK.-at-.pharm.cpb.uokhsc.edu

Date: Fri, 20 Feb 1998 14:36:33 CET

Subject: Re: PharmPK Half-life of drug elimination

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

X-pmrqc: 1

Priority: normal

To the PharmPK group:

With respect to the distribution of half-lives: as indicated by Dr.

Jelliffe, assuming a log-normal distribution may be more appropriate

than a normal distribution. Actually, we know that many 'biological'

measures are log-normally distributed; at least, they are 'more log-

normal' than 'normal' (in case of bimodial distributions, both the

log-normal and the normal assumption will be incorrect as well; see

Dr. Jelliffe's message).

Apart from being a distribution which may be expected to be more

closely to the true distribution, an attractive advantage of the log-

normal is that we don't need to care about the difference in the

distribution of rate constants and half-lives: they follow the same

distribution, and their mean values obey the rule

'half-life = ln(2) / k'.

Another advantage is, of course, that we never get negative,

'impossible' values for expected values and confidence intervals.

The disadvantages are (1) a slightly more complicated procedure in

the calculations, which cannot be done as easily as in case of a

normal distribution, in most software packages, and (2) you have to

justify the use of the log-normal distribution: The use of a normal

distribution is so widespread in our world that you can use it without

a sound justification (i.e., it seems to be generally accepted in

scientific papers); in general, you are expected to demonstrate

that the distribution does not deviate significantly from a normal

distribution; in general, this 'proof' is quite easy if you don't have

too much data. However, this does not imply that the distribution

have been shown to be normally distributed.

As you may understand from this, I have a strong preference for the

log-normal distribution, and I promote its use wherever possible

(and justified!).

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 - On 13 Mar 1998 at 09:58:38, "Susil F. Fernando" (fersf.aaa.cougar.vut.edu.au) sent the message

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Greetings!

Could someone recommend simulation software currently available

forPharmK & PharmDynamics calculations suitable for nursing courses?

Thank you in advance.

Regards,

Susil - On 16 Mar 1998 at 13:39:25, David_Bourne (david.-at-.pharm.cpb.uokhsc.edu) sent the message

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Date: Fri, 13 Mar 1998 17:51:53 -0600

From: "Dr. Gamal Hussein" <

Reply-To: GHussein-clinPharm.at.worldnet.att.net

MIME-Version: 1.0

To: PharmPK.-at-.pharm.cpb.uokhsc.edu

Subject: Re: PharmPK Re: AW: Half-life of drug elimination

Dear Susil:

Try "Practical Pharmacokinetics" program, you can get a free copy from

this site http://www.ClinPharmInt.com/

Gamal

Gamal Hussein, Pharm.D. at http://www.ClinPharmInt.com/Hussein.htm

Associate Professor of Pharmacy

Northeast Louisiana University-Pharmacy School

Associate Professor of Neurology

Louisiana State University-Medical School

Clinical Coordinator of Clinical Pharmacy/Pharmacology Program

The Medical Center of Louisiana at New Orleans

http://www.ClinPharmInt.com/Orleans.htm

A free demo of the following programs is currently available

for evaluation. Click on the program title to download it. Our goal is

to provide the best tools for education and practice. Thanks for

visiting.

Design your own computerized interactive tests in minutes. This program

converts exams (files) written with any word processing programs to a

computerized/self-grading exam. It is also an excellent tool to

generate unlimited number of interactive case study. It is equipped

with a calculator, a calendar, and an instructor-defined password. It

also provides cumulative statistical reports on class/student

performance.

This is the winner of the 1996 American Association of Colleges of

Pharmacy-Innovation in Teaching Competition. It was designed for the

teaching and practice of clinical pharmacokinetics. It is currently

used by educators and clinicians in more than 45 countries worldwide.

The following programs will be available very soon. Please, e

mail us if you have an interest in them.

---

X-Sender: jelliffe.-a-.hsc.usc.edu

Date: Fri, 13 Mar 1998 16:50:53 -0800

To: PharmPK.-at-.pharm.cpb.uokhsc.edu

From: Roger Jelliffe <

Subject: Re: PharmPK Re: AW: Half-life of drug elimination

Mime-Version: 1.0

Dear Susil:

You might consider the USC*PACK software. You can get info about it

from our web site below. There are also several other good packages

available, such as TDMS, MW/Pharm, and the Abbottbase software.

Roger Jelliffe

************************************************

Roger W. Jelliffe, M.D.

USC Lab of Applied Pharmacokinetics

CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033

Phone (213)342-1300, Fax (213)342-1302

email=3Djelliffe.-a-.hsc.usc.edu

************************************************

Take a look at our Web page for announcements of=20

new software and upcoming workshops and events!!

It is http://www.usc.edu/hsc/lab_apk/

************************************************

---

Date: Mon, 16 Mar 1998 12:52:54 -0500

From: kwatson <

Subject: PharmPK Re: AW: Half-life of drug elimination

Sender: kwatson <

To: "INTERNET:PharmPK.aaa.pharm.cpb.uokhsc.edu"

<

MIME-Version: 1.0

We currently sell a software called WinNonlin. It is the new standard

in pharmacokinetic, pharmacodynamic and noncompartmental analysis. Its

intuitive interface and flexible framework facilitates the use of this powerful

application and provide seamless interfacing with other

software and hardware. If you would like to see a demo of the software, please

send me your name and address and I will gladly send it out to you.=20 - On 17 Mar 1998 at 16:08:54, "David S. Farrier" (dfarrier.aaa.bright.net) sent the message

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Dear Susil,

Also of interest, you might look into "PK Solutions 2.0", an easy,

interactive and complete noncompartmental pharmacokinetics data analysis

system designed for researchers and educators. The program offers the bonus

feature of running in Excel providing unparalleled easy of use, data

exchange flexibility, and cross-platform compatibility. A demo is available

along with a free listing of 75 noncompartmental equations at our web site:

http://www.bright.net/~dfarrier

David S. Farrier, Ph.D.

Summit Research Services

Pharmacokinetics and Metabolism Software

1374 Hillcrest Drive

Ashland, OH 44805

Tel: 419-289-9207

Web: www.bright.net/~dfarrier

Email: dfarrier.-at-.bright.net

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