- On 13 Oct 2001 at 11:37:53, "Rahul Pradhan" (rahulprd.aaa.hotmail.com) sent the message

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Hi, I am a graduate student in Pharmaceutics. I am studying a course

in Non-parametric statistical methods. I am curious to know if

anybody can suggest me some examples in Pharmacokinetics where

non-parametric statistics has been applied. Please also suggest any

possible examples in the PK area where these methods may be needed.

Regards to all.

Rahul Pradhan - On 15 Oct 2001 at 23:39:47, "Gobburu, Jogarao V" (GOBBURUJ.-a-.cder.fda.gov) sent the message

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The following message was posted to: PharmPK

Dear Rahul,

Nonparametric statistics are employed in pkpd related areas reasonably

frequently but not as frequently as parametric statistics. I have seen

their use in:

1. Statistical testing to compare two distributions.

Example: Kolmogorov-Smirnov test

2. Population PKPD analyses.

Example: http://lapk3.hsc.usc.edu/lapk/

3. Frequency calculations for complicated scenarios, where the probability

is determined by shear computational force, especially when the underlying

statistical distribution is under question.

Example: Re-randomization/permutation tests, nonparametric bootstrap, etc.

Regards,

Joga Gobburu,

Pharmacometrics,

CDER, FDA - On 16 Oct 2001 at 11:23:14, David Bourne (david.aaa.boomer.org) sent the message

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[Two replies - db]

From: BEDDING_ALUN.aaa.LILLY.COM

Date: Mon, 15 Oct 2001 08:38:15 +0100

To: david.at.boomer.org

Subject: Re: PharmPK

Dear Rahul,

The most obvious use of non-parametric methods is in the analysis of

the time to maximum concentration (tmax), which is dependent on the

sampling interval and therefore rarely fufils the assumptions for a

parametric assessment.

A useful reference for the non-parametric assessment in a

bioequivalence study is:

Hauschke D, Steinijans VW, and Diletti E (1990) A distribution free

procedure for the statistical analysis of bioequivalence

studiesInternational Journal of Clinical Pharmacology, Therapy and

Toxicology, 28, 72-8

Kind regards,

Alun Bedding

Senior Statistician, Clinical Pharamacology Regulatory and Scientific Expert

Eli Lilly

---

From: "Federico Lerner, MD"

Date: Mon, 15 Oct 2001 09:55:05 -0300

To: david.at.boomer.org

Subject: RE: Applications of Non-parametric methods

The following message was posted to: PharmPK

Dear Rahul,

Non-parametrics statistics are appliable for the analyses of non-nermal

metabolites Pk profile. This is applicalbe in cases of different

metabilizers phenotype, fluoxetine as example. This is because at least two

different subpopulations are present.

Regards

Federico Lerner, MD - On 17 Oct 2001 at 23:02:59, Helmut =?iso-8859-1?Q?Sch=FCtz?= (helmut.schuetz.-at-.chello.at) sent the message

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The following message was posted to: PharmPK

Dear Rahul,

Nonparametrics are mandatory for measurements originating from discrete

distributions (e.g., tmax). This is also mentioned in the current EU-guidance

(July 2001) for the investigation of bioavailability and bioequivalence, which

can be obtained from EMEA:

http://www.emea.eu.int/pdfs/human/ewp/140198en.pdf

If you plan and evaluate a confirmatory study solely on nonparametrics (yes,

AUC, cmax,...), everything is fine too (our sponsors got approvals with about

300 BA/BE-studies).

Some more references:

Steinijans, V.W. and D. Hauschke;

Update on the statistical analysis of bioequivalence studies

Int. J. Clin. Pharm. Ther. Toxicol. 28, 105-110 (1990)

Vuorinen, J. and J. Turunen;

A Simple Three-Step Procedure for Parametric and Nonparametric Assessment of

Bioequivalence

Drug Information Journal 31/1, 167-180 (1997)

Nonparametrical methods may also be useful in all areas, where a

formal prove of

distributional assumptions may either not be possible, or lack of statistical

power (e.g., if sample sizes are below appr. 30). The assymptotic efficacy of

many nonparametric methods is 3/pi=95% if the underlying distribution

is normal.

If distributions are 'heavy tailed' (which is actually very often the case in

the 'real world'), nonparametric methods will perform superior to their

parametric analogues.

Yet another reference:

Abebe, A., Crimin, K. and J.K. McKean;

Rank-Based Procedures for Linear Models: Applications to Pharmaceutical Science

Data

Drug Information Journal 35/3, 947-971 (2001)

They have also run a very nice web-site, were you can input your own data...

http://www.stat.wmich.edu/slab/RGLM/

Best regards,

Helmut Schuetz

Head biometrics

Biokinet GmbH

Nattergasse 4

A-1170 Vienna/Austria

tel +43(0)1 4856969-77

fax +43(0)1 4856970-90

email helmut.schuetz.aaa.chello.at - On 18 Oct 2001 at 13:43:00, Roger Jelliffe (jelliffe.aaa.hsc.usc.edu) sent the message

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Dear Rahul:

Yes, nonparametric (NP) methods are very useful in population

PK/PD modeling, as they are not constrained by any assumptions of

normality or lognormality in the parameter distributions. Because of

this, they can detect unsuspected subpopulations such as fast or slow

metabolizers. The methods are also consistent - that is, the more you

sample from the population, the more the results approach the true

results.

NP models are also best suited for acting on the basis of the

population information and data, using the new method of "multiple

model" dosage design, which evaluates the predicted precision with

which any dosage regimen with achieve a desired target goal, and

specifically designs the regimen which achieves the goal with maximal

precision. This is especially useful then the parameter distributions

are not Gaussian, but have genetic polymorphism, as so many do.

More info is on our web site www.lapk.org, under teaching

topics, and under old workshop sand presentations. You can download a

lot of stuff there.

Very best regards,

Roger Jelliffe

Roger W. Jelliffe, M.D. Professor of Medicine, USC

USC Laboratory of Applied Pharmacokinetics

2250 Alcazar St, Los Angeles CA 90033, USA

Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.hsc.usc.edu

Our web site= http://www.usc.edu/hsc/lab_apk

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