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Colleagues
We are currently planning validation of our standard
pharmacokinetic software packages. Do any of you have experience
with the validation of WinNONLIN ?
Thanks.
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[Two replies - db]
Date: Tue, 02 May 2000 14:02:15 +1200
From: Nick Holford
X-Accept-Language: en
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Validation of PK software
I received a copy of WinNonLin today. Included in the packing materials
was a letter dated December 15 1999 from RL Chamberlain, Executive
Consultant Services Inc to Jessie Herr, Pharsight corp.
This reads:
"I have completed the audit of WinNonlin through version 3.1. During the
site visit the Validation Documentation along with the relevant Standard
Operating Procedures (SOPs) were reviewed. Pharsight has successfully
addressed all issues raised."
"It is my belief that the development and maintenance of this product
satisfies current industry understanding of the regulatory requirements
for Computer Systems Validation"
Good enough for Government work?
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
Date: Tue, 02 May 2000 15:54:02 -0700
From: Jessie Herr
Organization: Pharsight Corp.
X-Accept-Language: en
To: PharmPK.-a-.boomer.org
Subject: Re: PharmPK Validation of PK software
About validation of WinNonlin:
Richard L. Chamberlain, a well known computer systems validation expert,
audits each major release of WinNonlin and WinNonMix and provides a
certificate that the development and maintenance of the product
satisfies current industry understanding of the regulatory requirements
for Computer Systems Validation.
In addition, Pharsight offers a Validation Kit for WinNonlin,
independently developed by Richard L. Chamberlain, for use by its
customers to aid in validating installations of WinNonlin in their
environments.
.... Jessie Herr, Manager, QA, Pharsight Corp.
--
Jessie Herr, Ph.D. jessie.aaa.pharsight.com
Tel: 650-314-3830 Fax: 650-314-3810
Pharsight Corp.
800 West El Camino, Suite 200
Mountain View, CA 94040
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However it would appear that RL Chamberlain did not address the FDA regulations
when he did his audit as we have just received an email from Pharsight this
morning.
Although not strictly the same as validation of the computer system it might be
of interest.
Presently no version of WinNonlin is compliant with Rule 21 CFR Part
11. In our
environment
the FDA are demanding compliance with electronic signatures and data tracking.
Nick Holford made a nice comment
'Good enough for Government work?'
In answer to this Nick, I would say No. Not if you have to use the work for an
FDA submission.
Here is the message we received from Pharsight, please note that we have to be
compliant by 2001,
that means SAS will also have to be upgraded !
=============================email from
Pharsight===============================
Sorry for the delay in getting back to you. We've been getting a lot of queries
on
this topic lately.
You will probably want to check our web site (http://www.pharsight.com) which
has a
statement concerning software validation and 21CFR11 compliance. Note that they
are
really separate topics.
At present, WinNonlin in any form does not support 21CFR11. You will need to
track
your results manually as you probably have already been doing. Basically, it is
exactly as compliant as SAS.
We are currently starting the next version of the product, which will be
explicitly
21CFR11 compliant, supporting a paperless licensing submission. Since we are in
the
beginning stages, this is an excellent time for customer input.
How would you like WinNonlin to behave to meet your expectations of compliance
with
the regulation? Any thoughts or suggestions would be helpful.
Sincerely,
Russell Reeve
Pharsight Technical Support
p.s. Russell, in case you get more enquiries due to this, I am sorry, but some
of the information may
be of use to you and others in PharmPK world.
Anton.
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Since my note to this group started some discussions, I thought I should
provide some clarification. These are topics that we at Pharsight have
thought about so I am providing some material from our web site
(www.pharsight.com).
GLP/GCP/GAMP Compliance
Pharsight's products, including WinNonlin and WinNonMix, are widely used
by pharmaceutical companies, academic and research institutions, as well
as regulatory agencies. Several of these organizations have audited and
approved Pharsight's software and development methods as suitable for
use under their GLP, GCP, and GAMP compliance/standards. Pharsight's
products are developed using standard, well-documented Software
Development Life Cycle (SDLC) processes and procedures, to enable users
of Pharsight's products to be GLP/GCP/GAMP compliant. Pharsight
systematically validates its products as part of its software
development and delivery process.
21 CFR Part 11 Compliance
Pharsight is also working with our customers to help them achieve
compliance with 21 CFR Part 11 (Electronic Records; Electronic
Signatures; Final Rule) regulations. The Enterprise Editions of
WinNonlin and WinNonMix are initial steps toward achieving this
compliance which can be implemented today, allowing users to read PK/PD
data and save analysis results directly to/from a secure centralized
database protected by user login procedures. Pharsight is also
developing a secure repository for PK/PD data and analysis results from
WinNonlin, WinNonMix, and other analysis tools in the form of the PK
Database product.
If you have further questions or comments, please contact me directly.
.... Jessie Herr, Manager, QA, Pharsight Corp.
--
Jessie Herr, Ph.D. jessie.at.pharsight.com
Tel: 650-314-3830 Fax: 650-314-3810
Pharsight Corp.
800 West El Camino, Suite 200
Mountain View, CA 94040
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Hi:
Does someone know how, when to monitoring Digoxin level will be more
effective??
and is there any guideline for monitoring Digoxin level, please tell me...
Thanks..E Chen PharmD
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Dear Dr. Chen:
About digoxin levels. It haas been customary to get them at the trough.
However, trough levels in general are the least informative when making an
individualized PK model, as they are carefully chosen so that the errors of
knowing when the level was drawn in relation to the dose make the least
difference. For that reason, trough levels by themselves are not that
useful in making an individual Bayesian PK model of the behavior of digoxin
in a patient. What you rreally want to do, I think, is to make a good
individual PK model of the behavior of the drug in that patient. It is
often useful to get other levels, for example, at the peak, about 1 3/4 hrs
after the dose. There is NO NEED AT ALL TO WAIT FOR DISTRIBUTION TO BE
COMPLETE. All that went out with linear regresion on the logs of the levels
- a very obsolete approach, and one limited to a 1 compartment model.
Further, it is good to take advantage of the excellent model of digoxin
made by Reuning and his colleagues, in which they clearly show that the
inotropic effect correlates much better with the amount of drug in the
peripheral nonserum compartment than with the serum levels. We have used
this model in the USC*PACK programs fo help guide digoxin therapy for many
years, and have found it most useful. You might look at an article by our
group in Therapeutic Drug Monitoring, 15: 380-393, 1993. It is a general
discussion of what we think TDM is about, and there is an interesting
example of digoxin there. I would look forward to talking with you more
about all this.
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.at.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
**********
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Dear Erik,
Sample 12-24 hours post administration. Also see Chap. 20; Applied
Pharmacokinetics, Evans et al; Applied Therapeutics Inc, 1992
Sri
Srikumaran Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
203 B Katz Hall, School of Pharmacy
5005 Rockhill Road
Kansas City, MO 64110
816-235-1794 (voice); 816-235-5190 (fax)
-----Original Message-----
Hi:
Does someone know how, when to monitoring Digoxin level will be more
effective??
and is there any guideline for monitoring Digoxin level, please tell me...
Thanks..E Chen PharmD---
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Dear Sri and Eric:
If you sample only 12-24 hours after a dose, you miss much of
the dynamics
you might wish to capture, and your parameter estimates may not be as
precise as they might be when you fit an individualized model to the data.
There is no need to avoid getting levels during the distributional phase.
D-optimal design is a very underused strategy clinically, but
most useful.
It has been around for about 30 years now. See D'Argenio DZ, Optimal Times
for Pharmacokinetic Experiments, J. Pharmacokin + Biopharmaceut, 9:
739-755, 1981. This strategy is designed to get levels at the times when
they will result in the most precise parameter values in the model you have
chosen to use to describe the behavior of the drug. The catch-22 is that
you are supposed to know the prameter values in order to compute the
optimal times to find them. However, if you are using a population model as
the Bayesian prior, the optimal times for it will very likely be pretty
reasonable to use. D-optimal design has become popular in the drug industry
to maximize the information obtained from the fewest levels in a study.
For digoxin, we have found that the peak level from an oral dose is
reached at about 1.75 hours. This, plus a trough, is a good general pair of
levels to use. Do not interpret the meaning of a peak level as if it were a
trough, as it is in the distributional phase. But it and a trough will give
a good data set to make an individualized model from, if you use the 2
compartment model of Reuning and colleagues. For the exchange rate
constants out to and back from the peripheral compartment, we think that
levels at 1/2 hour after the oral dose, and also at 7 hours, and good ones
for perceiving these rate constants, and I have used these approaches
clinically and found them to give good models which were very helpful in
understanding what was going on with the drug in the patient. You ALWAYS
have to LOOK AT THE PATIENT. Nobody who ever wrote a book knows your
patient better than you do, and no author can evaluate YOUR patient's
clinical sensitivity to digoxin (or any other drug) better than you. Based
on this, and on your clinical judgment and perception of how much your
patient needs the drug, set your target goal, either in the peripheral
compartment (usually the best), or as a target trough serum concentration.
Then compute the dosage regimen to best achieve your goal (hit the target).
That's what TDM is about, we think, in our lab. Serum levels alone do not
begin to tell you what you really need to know, especially when you are
using a drug like digoxin, where the clinical effect is most closely
correlated not with the serum level, but with the peripheral compartment
concentration.
Hope this helps,
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.aaa.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
*************
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