Hi,
I have a data set containing PK concentrations and PD effect.
When plotting PD as a function of PD a clear anti-clockwise hysteresis
plot appears.
I would like to get a (rough) estimate of the PD time delay w.r.t. the PK
without
using a compartmental description for the observed PK, even not using
a polynomal function that fits the PK. The assumption I make is that
all PD delay can be explained by the delay through an effect compartment.
I am wondering if methods exist that solely use the raw data to
calculate such time delays.
Thank you for any comment/suggestion,
Jos
Jos Lommerse
Modeler Consultant
Quantitative Solutions BV
Molenweg 79
5349 AC Oss
The Netherlands
[email protected]<mailto:[email protected]>
+31 412 211102
Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
New Jersey, USA 07033), and/or its affiliates Direct contact information
for affiliates is available at
http://www.merck.com/contact/contacts.html) that may be confidential,
proprietary copyrighted and/or legally privileged. It is intended solely
for the use of the individual or entity named on this message. If you are
not the intended recipient, and have received this message in error,
please notify us immediately by reply e-mail and then delete it from
your system.
Estimation of ke0 from raw data
Hi Jos,
Why not try the indirect response model instead? The fixed effects are more
interpretable pharmacologically than just using Ke0.
The initial estimate of the first order rate constant of degradation (kout) of
response could be the slope of the decline of the response when plotted with
time.
You can read more in detail as there is lot of literature if you are not
familiar with these models.
Best
Mukul Minocha
Quoted reply history
> On 05-Sep-2015, at 13:43, Lommerse, JPM (Jos) <[email protected]> wrote:
>
> Hi,
>
> I have a data set containing PK concentrations and PD effect.
> When plotting PD as a function of PD a clear anti-clockwise hysteresis
> plot appears.
> I would like to get a (rough) estimate of the PD time delay w.r.t. the PK
> without
> using a compartmental description for the observed PK, even not using
> a polynomal function that fits the PK. The assumption I make is that
> all PD delay can be explained by the delay through an effect compartment.
> I am wondering if methods exist that solely use the raw data to
> calculate such time delays.
>
> Thank you for any comment/suggestion,
>
> Jos
>
> Jos Lommerse
> Modeler Consultant
> Quantitative Solutions BV
> Molenweg 79
> 5349 AC Oss
> The Netherlands
> [email protected]
> +31 412 211102
>
>
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> New Jersey, USA 07033), and/or its affiliates Direct contact information
> for affiliates is available at
> http://www.merck.com/contact/contacts.html) that may be confidential,
> proprietary copyrighted and/or legally privileged. It is intended solely
> for the use of the individual or entity named on this message. If you are
> not the intended recipient, and have received this message in error,
> please notify us immediately by reply e-mail and then delete it from
> your system.
Hi Jos,
Leonid has a post on it from some time ago, where he shows code to do
indeed linear interpolation.
see http://www.cognigencorp.com/nonmem/current/2008-January/4167.html
See also some older thread that discusses more possibilities:
http://www.cognigencorp.com/nonmem/nm/99sep241996.html
Anyway, it comes down to storing the current and previous concentration,
calculating the slope and with these parameters, interpolate in the $DES
block with T for time.
Hope this helps,
Jeroen
--
http://pd-value.com
[email protected]
@PD_value
+31 6 23118438
-- More value out of your data!
Quoted reply history
On 09/05/2015 08:44 PM, Lommerse, JPM (Jos) wrote:
>
> Dear Samer,
>
>
>
> Thank you for the reference.
>
> However, the method of Fuseau assumes
>
> that a mathematical description for
>
> the PK curve is available.
>
>
>
> I would like to do without such a PK description
>
> and directly use the PK observations, e.g. applying
>
> linear interpolation between the PK data points.
>
> Would that be feasible?
>
>
>
> Thanks, Jos
>
>
>
> *From:*Samer Mouksassi [mailto:[email protected]]
> *Sent:* Saturday, September 05, 2015 8:34 PM
> *To:* Lommerse, JPM (Jos); [email protected]
> *Subject:* RE: Estimation of ke0 from raw data
>
>
>
>
>
> Dear Jos,
>
> Please have a look at the algorithm detailed in the appendix of this
> publication:
>
> Fuseau E, Sheiner LB.
>
> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
> nonparametric pharmacodynamic model.
>
> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
>
> Regards,
>
> Samer
>
>
>
>
>
> *From:* [email protected]
> <mailto:[email protected]>
> [mailto:[email protected]] *On Behalf Of *Lommerse, JPM (Jos)
> *Sent:* Saturday, September 5, 2015 1:44 PM
> *To:* [email protected] <mailto:[email protected]>
> *Subject:* [NMusers] Estimation of ke0 from raw data
>
>
>
> Hi,
>
>
>
> I have a data set containing PK concentrations and PD effect.
>
> When plotting PD as a function of PD a clear anti-clockwise hysteresis
>
> plot appears.
>
> I would like to get a (rough) estimate of the PD time delay w.r.t. the
> PK without
>
> using a compartmental description for the observed PK, even not using
>
> a polynomal function that fits the PK. The assumption I make is that
>
> all PD delay can be explained by the delay through an effect compartment.
>
> I am wondering if methods exist that solely use the raw data to
>
> calculate such time delays.
>
>
>
> Thank you for any comment/suggestion,
>
>
>
> Jos
>
>
>
> *Jos Lommerse*
>
> Modeler Consultant
>
> /Quantitative Solutions BV/
>
> /Molenweg 79/
>
> /5349 AC Oss/
>
> /The Netherlands/
>
> [email protected] <mailto:[email protected]>
>
> +31 412 211102
>
>
>
>
>
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> New Jersey, USA 07033), and/or its affiliates Direct contact information
> for affiliates is available at
> http://www.merck.com/contact/contacts.html) that may be confidential,
> proprietary copyrighted and/or legally privileged. It is intended solely
> for the use of the individual or entity named on this message. If you are
> not the intended recipient, and have received this message in error,
> please notify us immediately by reply e-mail and then delete it from
> your system.
>
>
>
> *NOTICE: *The information contained in this electronic mail message is
> intended only for the personal and confidential use of the designated
> recipient(s) named above. This message may be an attorney-client
> communication, may be protected by the work product doctrine, and may
> be subject to a protective order. As such, this message is privileged
> and confidential. If the reader of this message is not the intended
> recipient or an agent responsible for delivering it to the intended
> recipient, you are hereby notified that you have received this message
> in error and that any review, dissemination, distribution, or copying
> of this message is strictly prohibited. If you have received this
> communication in error, please notify us immediately by telephone and
> e-mail and destroy any and all copies of this message in your
> possession (whether hard copies or electronically stored copies).
> Thank you.
>
>
> buSp9xeMeKEbrUze
>
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> New Jersey, USA 07033), and/or its affiliates Direct contact information
> for affiliates is available at
> http://www.merck.com/contact/contacts.html) that may be confidential,
> proprietary copyrighted and/or legally privileged. It is intended solely
> for the use of the individual or entity named on this message. If you are
> not the intended recipient, and have received this message in error,
> please notify us immediately by reply e-mail and then delete it from
> your system.
>
Jos,
It is not very clear what exactly you need. If you can use modeling tools, then linear interpolation + effect compartment + Emax model for the effect compartment versus PD dependence should work. If you would like to use only the raw data, no modeling, NCA style analysis, then the difference between Tmax of PK and Tmax of PD could be used as a crude estimate of the delay. Or you can use hysteresis curve for the PK curve with the time delay (with linear interpolation) and PD, and change the time delay for PK part until the hysteresis would disappear (using some metrics what does it mean "disappear"; may be area inside the loop is small). The time shift that provides smallest hysteresis area is the delay time.
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Quoted reply history
On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
> Dear Samer,
>
> Thank you for the reference.
>
> However, the method of Fuseau assumes
>
> that a mathematical description for
>
> the PK curve is available.
>
> I would like to do without such a PK description
>
> and directly use the PK observations, e.g. applying
>
> linear interpolation between the PK data points.
>
> Would that be feasible?
>
> Thanks, Jos
>
> *From:*Samer Mouksassi [mailto:[email protected]]
> *Sent:* Saturday, September 05, 2015 8:34 PM
> *To:* Lommerse, JPM (Jos); [email protected]
> *Subject:* RE: Estimation of ke0 from raw data
>
> Dear Jos,
>
> Please have a look at the algorithm detailed in the appendix of this
> publication:
>
> Fuseau E, Sheiner LB.
>
> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
> nonparametric pharmacodynamic model.
>
> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
>
> Regards,
>
> Samer
>
> *From:* [email protected]
> <mailto:[email protected]>
> [mailto:[email protected]] *On Behalf Of *Lommerse, JPM (Jos)
> *Sent:* Saturday, September 5, 2015 1:44 PM
> *To:* [email protected] <mailto:[email protected]>
> *Subject:* [NMusers] Estimation of ke0 from raw data
>
> Hi,
>
> I have a data set containing PK concentrations and PD effect.
>
> When plotting PD as a function of PD a clear anti-clockwise hysteresis
>
> plot appears.
>
> I would like to get a (rough) estimate of the PD time delay w.r.t. the
> PK without
>
> using a compartmental description for the observed PK, even not using
>
> a polynomal function that fits the PK. The assumption I make is that
>
> all PD delay can be explained by the delay through an effect compartment.
>
> I am wondering if methods exist that solely use the raw data to
>
> calculate such time delays.
>
> Thank you for any comment/suggestion,
>
> Jos
>
> *Jos Lommerse*
>
> Modeler Consultant
>
> /Quantitative Solutions BV/
>
> /Molenweg 79/
>
> /5349 AC Oss/
>
> /The Netherlands/
>
> [email protected] <mailto:[email protected]>
>
> +31 412 211102
>
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> New Jersey, USA 07033), and/or its affiliates Direct contact information
> for affiliates is available at
> http://www.merck.com/contact/contacts.html) that may be confidential,
> proprietary copyrighted and/or legally privileged. It is intended solely
> for the use of the individual or entity named on this message. If you are
> not the intended recipient, and have received this message in error,
> please notify us immediately by reply e-mail and then delete it from
> your system.
>
> *NOTICE: *The information contained in this electronic mail message is
> intended only for the personal and confidential use of the designated
> recipient(s) named above. This message may be an attorney-client
> communication, may be protected by the work product doctrine, and may be
> subject to a protective order. As such, this message is privileged and
> confidential. If the reader of this message is not the intended
> recipient or an agent responsible for delivering it to the intended
> recipient, you are hereby notified that you have received this message
> in error and that any review, dissemination, distribution, or copying of
> this message is strictly prohibited. If you have received this
> communication in error, please notify us immediately by telephone and
> e-mail and destroy any and all copies of this message in your possession
> (whether hard copies or electronically stored copies). Thank you.
>
> buSp9xeMeKEbrUze
>
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> New Jersey, USA 07033), and/or its affiliates Direct contact information
> for affiliates is available at
> http://www.merck.com/contact/contacts.html) that may be confidential,
> proprietary copyrighted and/or legally privileged. It is intended solely
> for the use of the individual or entity named on this message. If you are
> not the intended recipient, and have received this message in error,
> please notify us immediately by reply e-mail and then delete it from
> your system.
Ken Kowalski published a paper many years ago which I think he called a
semicompartmental method. It was not developed as a population approach and
only applies to single dose data but works really well under those conditions.
It was published in the Journal of Pharmacokinetics and Biopharmaceutics.
Pete Bonate.
Quoted reply history
> On Sep 5, 2015, at 4:37 PM, Leonid Gibiansky <[email protected]>
> wrote:
>
> Jos,
>
> It is not very clear what exactly you need. If you can use modeling tools,
> then linear interpolation + effect compartment + Emax model for the effect
> compartment versus PD dependence should work. If you would like to use only
> the raw data, no modeling, NCA style analysis, then the difference between
> Tmax of PK and Tmax of PD could be used as a crude estimate of the delay. Or
> you can use hysteresis curve for the PK curve with the time delay (with
> linear interpolation) and PD, and change the time delay for PK part until the
> hysteresis would disappear (using some metrics what does it mean "disappear";
> may be area inside the loop is small). The time shift that provides smallest
> hysteresis area is the delay time.
>
> Leonid
>
>
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: www.quantpharm.com
> e-mail: LGibiansky at quantpharm.com
> tel: (301) 767 5566
>
>
>
>> On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
>> Dear Samer,
>>
>> Thank you for the reference.
>>
>> However, the method of Fuseau assumes
>>
>> that a mathematical description for
>>
>> the PK curve is available.
>>
>> I would like to do without such a PK description
>>
>> and directly use the PK observations, e.g. applying
>>
>> linear interpolation between the PK data points.
>>
>> Would that be feasible?
>>
>> Thanks, Jos
>>
>> *From:*Samer Mouksassi [mailto:[email protected]]
>> *Sent:* Saturday, September 05, 2015 8:34 PM
>> *To:* Lommerse, JPM (Jos); [email protected]
>> *Subject:* RE: Estimation of ke0 from raw data
>>
>> Dear Jos,
>>
>> Please have a look at the algorithm detailed in the appendix of this
>> publication:
>>
>> Fuseau E, Sheiner LB.
>>
>> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
>> nonparametric pharmacodynamic model.
>>
>> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
>>
>> Regards,
>>
>> Samer
>>
>> *From:* [email protected]
>> <mailto:[email protected]>
>> [mailto:[email protected]] *On Behalf Of *Lommerse, JPM (Jos)
>> *Sent:* Saturday, September 5, 2015 1:44 PM
>> *To:* [email protected] <mailto:[email protected]>
>> *Subject:* [NMusers] Estimation of ke0 from raw data
>>
>> Hi,
>>
>> I have a data set containing PK concentrations and PD effect.
>>
>> When plotting PD as a function of PD a clear anti-clockwise hysteresis
>>
>> plot appears.
>>
>> I would like to get a (rough) estimate of the PD time delay w.r.t. the
>> PK without
>>
>> using a compartmental description for the observed PK, even not using
>>
>> a polynomal function that fits the PK. The assumption I make is that
>>
>> all PD delay can be explained by the delay through an effect compartment.
>>
>> I am wondering if methods exist that solely use the raw data to
>>
>> calculate such time delays.
>>
>> Thank you for any comment/suggestion,
>>
>> Jos
>>
>> *Jos Lommerse*
>>
>> Modeler Consultant
>>
>> /Quantitative Solutions BV/
>>
>> /Molenweg 79/
>>
>> /5349 AC Oss/
>>
>> /The Netherlands/
>>
>> [email protected] <mailto:[email protected]>
>>
>> +31 412 211102
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html) that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
>> *NOTICE: *The information contained in this electronic mail message is
>> intended only for the personal and confidential use of the designated
>> recipient(s) named above. This message may be an attorney-client
>> communication, may be protected by the work product doctrine, and may be
>> subject to a protective order. As such, this message is privileged and
>> confidential. If the reader of this message is not the intended
>> recipient or an agent responsible for delivering it to the intended
>> recipient, you are hereby notified that you have received this message
>> in error and that any review, dissemination, distribution, or copying of
>> this message is strictly prohibited. If you have received this
>> communication in error, please notify us immediately by telephone and
>> e-mail and destroy any and all copies of this message in your possession
>> (whether hard copies or electronically stored copies). Thank you.
>>
>>
>> buSp9xeMeKEbrUze
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html) that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
Semicompartmental method is implemented in WinNonlin Phoenix and sites Kowalski
and Karim (1995), A semicompartmental modeling approach for pharmacodynamic
data assessment, J Pharmacokinet Biopharm 23:307-22.
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Bonate, Peter
Sent: Saturday, September 05, 2015 5:40 PM
To: Leonid Gibiansky
Cc: Lommerse, JPM (Jos); Samer Mouksassi; [email protected]
Subject: Re: [NMusers] RE: Estimation of ke0 from raw data
Ken Kowalski published a paper many years ago which I think he called a
semicompartmental method. It was not developed as a population approach and
only applies to single dose data but works really well under those conditions.
It was published in the Journal of Pharmacokinetics and Biopharmaceutics.
Pete Bonate.
> On Sep 5, 2015, at 4:37 PM, Leonid Gibiansky
> <[email protected]<mailto:[email protected]>> wrote:
>
> Jos,
>
> It is not very clear what exactly you need. If you can use modeling tools,
> then linear interpolation + effect compartment + Emax model for the effect
> compartment versus PD dependence should work. If you would like to use only
> the raw data, no modeling, NCA style analysis, then the difference between
> Tmax of PK and Tmax of PD could be used as a crude estimate of the delay. Or
> you can use hysteresis curve for the PK curve with the time delay (with
> linear interpolation) and PD, and change the time delay for PK part until the
> hysteresis would disappear (using some metrics what does it mean "disappear";
> may be area inside the loop is small). The time shift that provides smallest
> hysteresis area is the delay time.
>
> Leonid
>
>
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: http://www.quantpharm.com
> e-mail: LGibiansky at http://quantpharm.com
> tel: (301) 767 5566
>
>
>
>> On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
>> Dear Samer,
>>
>> Thank you for the reference.
>>
>> However, the method of Fuseau assumes
>>
>> that a mathematical description for
>>
>> the PK curve is available.
>>
>> I would like to do without such a PK description
>>
>> and directly use the PK observations, e.g. applying
>>
>> linear interpolation between the PK data points.
>>
>> Would that be feasible?
>>
>> Thanks, Jos
>>
>> *From:*Samer Mouksassi [mailto:[email protected]]
>> *Sent:* Saturday, September 05, 2015 8:34 PM
>> *To:* Lommerse, JPM (Jos);
>> [email protected]<mailto:[email protected]>
>> *Subject:* RE: Estimation of ke0 from raw data
>>
>> Dear Jos,
>>
>> Please have a look at the algorithm detailed in the appendix of this
>> publication:
>>
>> Fuseau E, Sheiner LB.
>>
>> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
>> nonparametric pharmacodynamic model.
>>
>> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
>>
>> Regards,
>>
>> Samer
>>
>> *From:* [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>> [mailto:[email protected]] *On Behalf Of *Lommerse, JPM (Jos)
>> *Sent:* Saturday, September 5, 2015 1:44 PM
>> *To:* [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>> *Subject:* [NMusers] Estimation of ke0 from raw data
>>
>> Hi,
>>
>> I have a data set containing PK concentrations and PD effect.
>>
>> When plotting PD as a function of PD a clear anti-clockwise hysteresis
>>
>> plot appears.
>>
>> I would like to get a (rough) estimate of the PD time delay w.r.t. the
>> PK without
>>
>> using a compartmental description for the observed PK, even not using
>>
>> a polynomal function that fits the PK. The assumption I make is that
>>
>> all PD delay can be explained by the delay through an effect compartment.
>>
>> I am wondering if methods exist that solely use the raw data to
>>
>> calculate such time delays.
>>
>> Thank you for any comment/suggestion,
>>
>> Jos
>>
>> *Jos Lommerse*
>>
>> Modeler Consultant
>>
>> /Quantitative Solutions BV/
>>
>> /Molenweg 79/
>>
>> /5349 AC Oss/
>>
>> /The Netherlands/
>>
>> [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>>
>> +31 412 211102
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html)
>> that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
>> *NOTICE: *The information contained in this electronic mail message is
>> intended only for the personal and confidential use of the designated
>> recipient(s) named above. This message may be an attorney-client
>> communication, may be protected by the work product doctrine, and may be
>> subject to a protective order. As such, this message is privileged and
>> confidential. If the reader of this message is not the intended
>> recipient or an agent responsible for delivering it to the intended
>> recipient, you are hereby notified that you have received this message
>> in error and that any review, dissemination, distribution, or copying of
>> this message is strictly prohibited. If you have received this
>> communication in error, please notify us immediately by telephone and
>> e-mail and destroy any and all copies of this message in your possession
>> (whether hard copies or electronically stored copies). Thank you.
>>
>>
>> buSp9xeMeKEbrUze
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html)
>> that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
Hi Brian and others,
Thank you for all your replies. I’ve indeed found a solution in Phoenix. Using
Phoenix it was fairly simple to get an estimate on ke0
without using any assumption on the PK or PD (no time course PKPD model
needed), except for the effect compartment itself.
It is a quick manual try-and-error approach to collapse the hysteresis PK-PD
curve resulting in an estimate for ke0.
Kind regards,
Jos
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Sadler, Brian
Sent: Sunday, September 06, 2015 12:13 AM
To: [email protected]
Subject: RE: [NMusers] RE: Estimation of ke0 from raw data
Semicompartmental method is implemented in WinNonlin Phoenix and sites Kowalski
and Karim (1995), A semicompartmental modeling approach for pharmacodynamic
data assessment, J Pharmacokinet Biopharm 23:307-22.
From: [email protected]<mailto:[email protected]>
[mailto:[email protected]] On Behalf Of Bonate, Peter
Sent: Saturday, September 05, 2015 5:40 PM
To: Leonid Gibiansky
Cc: Lommerse, JPM (Jos); Samer Mouksassi;
[email protected]<mailto:[email protected]>
Subject: Re: [NMusers] RE: Estimation of ke0 from raw data
Ken Kowalski published a paper many years ago which I think he called a
semicompartmental method. It was not developed as a population approach and
only applies to single dose data but works really well under those conditions.
It was published in the Journal of Pharmacokinetics and Biopharmaceutics.
Pete Bonate.
> On Sep 5, 2015, at 4:37 PM, Leonid Gibiansky
> <[email protected]<mailto:[email protected]>> wrote:
>
> Jos,
>
> It is not very clear what exactly you need. If you can use modeling tools,
> then linear interpolation + effect compartment + Emax model for the effect
> compartment versus PD dependence should work. If you would like to use only
> the raw data, no modeling, NCA style analysis, then the difference between
> Tmax of PK and Tmax of PD could be used as a crude estimate of the delay. Or
> you can use hysteresis curve for the PK curve with the time delay (with
> linear interpolation) and PD, and change the time delay for PK part until the
> hysteresis would disappear (using some metrics what does it mean "disappear";
> may be area inside the loop is small). The time shift that provides smallest
> hysteresis area is the delay time.
>
> Leonid
>
>
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: http://www.quantpharm.com
> e-mail: LGibiansky at http://quantpharm.com
> tel: (301) 767 5566
>
>
>
>> On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
>> Dear Samer,
>>
>> Thank you for the reference.
>>
>> However, the method of Fuseau assumes
>>
>> that a mathematical description for
>>
>> the PK curve is available.
>>
>> I would like to do without such a PK description
>>
>> and directly use the PK observations, e.g. applying
>>
>> linear interpolation between the PK data points.
>>
>> Would that be feasible?
>>
>> Thanks, Jos
>>
>> *From:*Samer Mouksassi [mailto:[email protected]]
>> *Sent:* Saturday, September 05, 2015 8:34 PM
>> *To:* Lommerse, JPM (Jos);
>> [email protected]<mailto:[email protected]>
>> *Subject:* RE: Estimation of ke0 from raw data
>>
>> Dear Jos,
>>
>> Please have a look at the algorithm detailed in the appendix of this
>> publication:
>>
>> Fuseau E, Sheiner LB.
>>
>> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
>> nonparametric pharmacodynamic model.
>>
>> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
>>
>> Regards,
>>
>> Samer
>>
>> *From:* [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>> [mailto:[email protected]] *On Behalf Of *Lommerse, JPM (Jos)
>> *Sent:* Saturday, September 5, 2015 1:44 PM
>> *To:* [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>> *Subject:* [NMusers] Estimation of ke0 from raw data
>>
>> Hi,
>>
>> I have a data set containing PK concentrations and PD effect.
>>
>> When plotting PD as a function of PD a clear anti-clockwise hysteresis
>>
>> plot appears.
>>
>> I would like to get a (rough) estimate of the PD time delay w.r.t. the
>> PK without
>>
>> using a compartmental description for the observed PK, even not using
>>
>> a polynomal function that fits the PK. The assumption I make is that
>>
>> all PD delay can be explained by the delay through an effect compartment.
>>
>> I am wondering if methods exist that solely use the raw data to
>>
>> calculate such time delays.
>>
>> Thank you for any comment/suggestion,
>>
>> Jos
>>
>> *Jos Lommerse*
>>
>> Modeler Consultant
>>
>> /Quantitative Solutions BV/
>>
>> /Molenweg 79/
>>
>> /5349 AC Oss/
>>
>> /The Netherlands/
>>
>> [email protected]<mailto:[email protected]>
>> <mailto:[email protected]>
>>
>> +31 412 211102
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html) that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
>> *NOTICE: *The information contained in this electronic mail message is
>> intended only for the personal and confidential use of the designated
>> recipient(s) named above. This message may be an attorney-client
>> communication, may be protected by the work product doctrine, and may be
>> subject to a protective order. As such, this message is privileged and
>> confidential. If the reader of this message is not the intended
>> recipient or an agent responsible for delivering it to the intended
>> recipient, you are hereby notified that you have received this message
>> in error and that any review, dissemination, distribution, or copying of
>> this message is strictly prohibited. If you have received this
>> communication in error, please notify us immediately by telephone and
>> e-mail and destroy any and all copies of this message in your possession
>> (whether hard copies or electronically stored copies). Thank you.
>>
>>
>> buSp9xeMeKEbrUze
>>
>> Notice: This e-mail message, together with any attachments, contains
>> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>> New Jersey, USA 07033), and/or its affiliates Direct contact information
>> for affiliates is available at
>> http://www.merck.com/contact/contacts.html) that may be confidential,
>> proprietary copyrighted and/or legally privileged. It is intended solely
>> for the use of the individual or entity named on this message. If you are
>> not the intended recipient, and have received this message in error,
>> please notify us immediately by reply e-mail and then delete it from
>> your system.
>>
Dear Jos,
Although you have found a solution already, I would like to point to the
following publication:
Unadkat JD, Bartha F, Sheiner LB. Simultaneous modeling of
pharmacokinetics and pharmacodynamics with nonparametric kinetic and
dynamic models. Clin Pharmacol Ther 1986; 40: 86-93.
If I understand you correctly, this approach is exactly what you were
asking for. The PK, consisting of linear interpolation between the
observations, so purely nonparametric and noncompartmental, is used as
the driving force for the effect compartment concentration Ce with a
first-order rate constant ke0. Plotting Ce versus E gives a hysteresis
plot, and by adjusting ke0 the increasing and declining part of the
curve can be made to collapse. The PD model can be used parametrically
and nonparametrically.
I have applied this approach in several papers, also comparing various
approaches, e.g.
Proost JH, Schiere S, Eleveld DJ, Wierda JMKH. Simultaneous versus
sequential pharmacokinetic-pharmacodynamic population analysis using an
Iterative Two-Stage Bayesian technique. Biopharm Drug Dispos 2007;
28(8): 455-473.
I did not check whether this approach may the same method as used in
Phoenix.
best regards,
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University of Groningen
The Netherlands
Lommerse, JPM (Jos) schreef op 8-9-2015 om 15:38:
>
> Hi Brian and others,
>
> Thank you for all your replies. I’ve indeed found a solution in
> Phoenix. Using Phoenix it was fairly simple to get an estimate on ke0
>
> without using any assumption on the PK or PD (no time course PKPD
> model needed), except for the effect compartment itself.
>
> It is a quick manual try-and-error approach to collapse the hysteresis
> PK-PD curve resulting in an estimate for ke0.
>
> Kind regards,
>
> Jos
>
> *From:*owner-nmusers_at_globomaxnm.com
> [mailto:owner-nmusers_at_globomaxnm.com] *On Behalf Of *Sadler, Brian
> *Sent:* Sunday, September 06, 2015 12:13 AM
> *To:* nmusers_at_globomaxnm.com
> *Subject:* RE: [NMusers] RE: Estimation of ke0 from raw data
>
> Semicompartmental method is implemented in WinNonlin Phoenix and sites
> Kowalski and Karim (1995), A semicompartmental modeling approach for
> pharmacodynamic data assessment, J Pharmacokinet Biopharm 23:307-22.
>
> *From:*owner-nmusers_at_globomaxnm.com
> <mailto:owner-nmusers_at_globomaxnm.com>
> [mailto:owner-nmusers_at_globomaxnm.com] *On Behalf Of *Bonate, Peter
> *Sent:* Saturday, September 05, 2015 5:40 PM
> *To:* Leonid Gibiansky
> *Cc:* Lommerse, JPM (Jos); Samer Mouksassi; nmusers_at_globomaxnm.com
> <mailto:nmusers_at_globomaxnm.com>
> *Subject:* Re: [NMusers] RE: Estimation of ke0 from raw data
>
> Ken Kowalski published a paper many years ago which I think he called
> a semicompartmental method. It was not developed as a population
> approach and only applies to single dose data but works really well
> under those conditions. It was published in the Journal of
> Pharmacokinetics and Biopharmaceutics.
>
> Pete Bonate.
>
>
>
> > On Sep 5, 2015, at 4:37 PM, Leonid Gibiansky
> <lgibiansky_at_quantpharm.com <mailto:lgibiansky_at_quantpharm.com>> wrote:
> >
> > Jos,
> >
> > It is not very clear what exactly you need. If you can use modeling
> tools, then linear interpolation + effect compartment + Emax model for
> the effect compartment versus PD dependence should work. If you would
> like to use only the raw data, no modeling, NCA style analysis, then
> the difference between Tmax of PK and Tmax of PD could be used as a
> crude estimate of the delay. Or you can use hysteresis curve for the
> PK curve with the time delay (with linear interpolation) and PD, and
> change the time delay for PK part until the hysteresis would disappear
> (using some metrics what does it mean "disappear"; may be area inside
> the loop is small). The time shift that provides smallest hysteresis
> area is the delay time.
> >
> > Leonid
> >
> >
> >
> > --------------------------------------
> > Leonid Gibiansky, Ph.D.
> > President, QuantPharm LLC
> > web: www.quantpharm.com http://www.quantpharm.com
> > e-mail: LGibiansky at quantpharm.com http://quantpharm.com
> > tel: (301) 767 5566
> >
> >
> >
> >> On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
> >> Dear Samer,
> >>
> >> Thank you for the reference.
> >>
> >> However, the method of Fuseau assumes
> >>
> >> that a mathematical description for
> >>
> >> the PK curve is available.
> >>
> >> I would like to do without such a PK description
> >>
> >> and directly use the PK observations, e.g. applying
> >>
> >> linear interpolation between the PK data points.
> >>
> >> Would that be feasible?
> >>
> >> Thanks, Jos
> >>
> >> *From:*Samer Mouksassi [mailto:Samer.Mouksassi_at_certara.com]
> >> *Sent:* Saturday, September 05, 2015 8:34 PM
> >> *To:* Lommerse, JPM (Jos); nmusers_at_globomaxnm.com
> <mailto:nmusers_at_globomaxnm.com>
> >> *Subject:* RE: Estimation of ke0 from raw data
> >>
> >> Dear Jos,
> >>
> >> Please have a look at the algorithm detailed in the appendix of this
> >> publication:
> >>
> >> Fuseau E, Sheiner LB.
> >>
> >> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
> >> nonparametric pharmacodynamic model.
> >>
> >> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
> >>
> >> Regards,
> >>
> >> Samer
> >>
> >> *From:* owner-nmusers_at_globomaxnm.com
> <mailto:owner-nmusers_at_globomaxnm.com>
> >> <mailto:owner-nmusers_at_globomaxnm.com>
> >> [mailto:owner-nmusers_at_globomaxnm.com] *On Behalf Of *Lommerse, JPM
> (Jos)
> >> *Sent:* Saturday, September 5, 2015 1:44 PM
> >> *To:* nmusers_at_globomaxnm.com <mailto:nmusers_at_globomaxnm.com>
> <mailto:nmusers_at_globomaxnm.com>
> >> *Subject:* [NMusers] Estimation of ke0 from raw data
> >>
> >> Hi,
> >>
> >> I have a data set containing PK concentrations and PD effect.
> >>
> >> When plotting PD as a function of PD a clear anti-clockwise hysteresis
> >>
> >> plot appears.
> >>
> >> I would like to get a (rough) estimate of the PD time delay w.r.t. the
> >> PK without
> >>
> >> using a compartmental description for the observed PK, even not using
> >>
> >> a polynomal function that fits the PK. The assumption I make is that
> >>
> >> all PD delay can be explained by the delay through an effect
> compartment.
> >>
> >> I am wondering if methods exist that solely use the raw data to
> >>
> >> calculate such time delays.
> >>
> >> Thank you for any comment/suggestion,
> >>
> >> Jos
> >>
> >> *Jos Lommerse*
> >>
> >> Modeler Consultant
> >>
> >> /Quantitative Solutions BV/
> >>
> >> /Molenweg 79/
> >>
> >> /5349 AC Oss/
> >>
> >> /The Netherlands/
> >>
> >> jlommerse_at_wequantify.com <mailto:jlommerse_at_wequantify.com>
> <mailto:jlommerse_at_wequantify.com>
> >>
> >> +31 412 211102
> >>
> >> Notice: This e-mail message, together with any attachments, contains
> >> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> >> New Jersey, USA 07033), and/or its affiliates Direct contact
> information
> >> for affiliates is available at
> >> http://www.merck.com/contact/contacts.html)
> http://www.merck.com/contact/contacts.html%29 that may be confidential,
> >> proprietary copyrighted and/or legally privileged. It is intended
> solely
> >> for the use of the individual or entity named on this message. If
> you are
> >> not the intended recipient, and have received this message in error,
> >> please notify us immediately by reply e-mail and then delete it from
> >> your system.
> >>
> >> *NOTICE: *The information contained in this electronic mail message is
> >> intended only for the personal and confidential use of the designated
> >> recipient(s) named above. This message may be an attorney-client
> >> communication, may be protected by the work product doctrine, and
> may be
> >> subject to a protective order. As such, this message is privileged and
> >> confidential. If the reader of this message is not the intended
> >> recipient or an agent responsible for delivering it to the intended
> >> recipient, you are hereby notified that you have received this message
> >> in error and that any review, dissemination, distribution, or
> copying of
> >> this message is strictly prohibited. If you have received this
> >> communication in error, please notify us immediately by telephone and
> >> e-mail and destroy any and all copies of this message in your
> possession
> >> (whether hard copies or electronically stored copies). Thank you.
> >>
> >>
> >> buSp9xeMeKEbrUze
> >>
> >> Notice: This e-mail message, together with any attachments, contains
> >> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
> >> New Jersey, USA 07033), and/or its affiliates Direct contact
> information
> >> for affiliates is available at
> >> http://www.merck.com/contact/contacts.html)
> http://www.merck.com/contact/contacts.html%29 that may be confidential,
> >> proprietary copyrighted and/or legally privileged. It is intended
> solely
> >> for the use of the individual or entity named on this message. If
> you are
> >> not the intended recipient, and have received this message in error,
> >> please notify us immediately by reply e-mail and then delete it from
> >> your system.
> >>
>
>
>
>
Dear Jos,
Although you have found a solution already, I would like to point to the following publication:
Unadkat JD, Bartha F, Sheiner LB. Simultaneous modeling of pharmacokinetics and pharmacodynamics with nonparametric kinetic and dynamic models. Clin Pharmacol Ther 1986; 40: 86-93.
If I understand you correctly, this approach is exactly what you were asking for. The PK, consisting of linear interpolation between the observations, so purely nonparametric and noncompartmental, is used as the driving force for the effect compartment concentration Ce with a first-order rate constant ke0. Plotting Ce versus E gives a hysteresis plot, and by adjusting ke0 the increasing and declining part of the curve can be made to collapse. The PD model can be used parametrically and nonparametrically.
I have applied this approach in several papers, also comparing various approaches, e.g.
Proost JH, Schiere S, Eleveld DJ, Wierda JMKH. Simultaneous versus sequential pharmacokinetic-pharmacodynamic population analysis using an Iterative Two-Stage Bayesian technique. Biopharm Drug Dispos 2007; 28(8): 455-473.
I did not check whether this approach may the same method as used in Phoenix.
best regards,
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University of Groningen
The Netherlands
Lommerse, JPM (Jos) schreef op 8-9-2015 om 15:38:
> Hi Brian and others,
>
> Thank you for all your replies. I’ve indeed found a solution in Phoenix. Using Phoenix it was fairly simple to get an estimate on ke0
>
> without using any assumption on the PK or PD (no time course PKPD model needed), except for the effect compartment itself.
>
> It is a quick manual try-and-error approach to collapse the hysteresis PK-PD curve resulting in an estimate for ke0.
>
> Kind regards,
>
> Jos
>
> *From:* [email protected] [ mailto: [email protected] ] *On Behalf Of *Sadler, Brian
>
> *Sent:* Sunday, September 06, 2015 12:13 AM
> *To:* [email protected]
> *Subject:* RE: [NMusers] RE: Estimation of ke0 from raw data
>
> Semicompartmental method is implemented in WinNonlin Phoenix and sites Kowalski and Karim (1995), A semicompartmental modeling approach for pharmacodynamic data assessment, J Pharmacokinet Biopharm 23:307-22.
>
> *From:* [email protected] < mailto: [email protected] > [ mailto: [email protected] ] *On Behalf Of *Bonate, Peter
>
> *Sent:* Saturday, September 05, 2015 5:40 PM
> *To:* Leonid Gibiansky
>
> *Cc:* Lommerse, JPM (Jos); Samer Mouksassi; [email protected] < mailto: [email protected] >
>
> *Subject:* Re: [NMusers] RE: Estimation of ke0 from raw data
>
> Ken Kowalski published a paper many years ago which I think he called a semicompartmental method. It was not developed as a population approach and only applies to single dose data but works really well under those conditions. It was published in the Journal of Pharmacokinetics and Biopharmaceutics.
>
> Pete Bonate.
>
> > On Sep 5, 2015, at 4:37 PM, Leonid Gibiansky < [email protected] < mailto: [email protected] >> wrote:
>
> >
> > Jos,
> >
>
> > It is not very clear what exactly you need. If you can use modeling tools, then linear interpolation + effect compartment + Emax model for the effect compartment versus PD dependence should work. If you would like to use only the raw data, no modeling, NCA style analysis, then the difference between Tmax of PK and Tmax of PD could be used as a crude estimate of the delay. Or you can use hysteresis curve for the PK curve with the time delay (with linear interpolation) and PD, and change the time delay for PK part until the hysteresis would disappear (using some metrics what does it mean "disappear"; may be area inside the loop is small). The time shift that provides smallest hysteresis area is the delay time.
>
> >
> > Leonid
> >
> >
> >
> > --------------------------------------
> > Leonid Gibiansky, Ph.D.
> > President, QuantPharm LLC
> > web: www.quantpharm.com http://www.quantpharm.com
> > e-mail: LGibiansky at quantpharm.com http://quantpharm.com
> > tel: (301) 767 5566
> >
> >
> >
> >> On 9/5/2015 2:44 PM, Lommerse, JPM (Jos) wrote:
> >> Dear Samer,
> >>
> >> Thank you for the reference.
> >>
> >> However, the method of Fuseau assumes
> >>
> >> that a mathematical description for
> >>
> >> the PK curve is available.
> >>
> >> I would like to do without such a PK description
> >>
> >> and directly use the PK observations, e.g. applying
> >>
> >> linear interpolation between the PK data points.
> >>
> >> Would that be feasible?
> >>
> >> Thanks, Jos
> >>
> >> *From:*Samer Mouksassi [mailto:[email protected]]
> >> *Sent:* Saturday, September 05, 2015 8:34 PM
>
> >> *To:* Lommerse, JPM (Jos); [email protected] < mailto: [email protected] >
>
> >> *Subject:* RE: Estimation of ke0 from raw data
> >>
> >> Dear Jos,
> >>
> >> Please have a look at the algorithm detailed in the appendix of this
> >> publication:
> >>
> >> Fuseau E, Sheiner LB.
> >>
> >> Simultaneous modeling of pharmacokinetics and pharmacodynamics with a
> >> nonparametric pharmacodynamic model.
> >>
> >> Clin Pharmacol Ther. 1984 Jun;35(6):733-41.
> >>
> >> Regards,
> >>
> >> Samer
> >>
>
> >> *From:* [email protected] < mailto: [email protected] >
>
> >> <mailto:[email protected]>
>
> >> [ mailto: [email protected] ] *On Behalf Of *Lommerse, JPM (Jos)
>
> >> *Sent:* Saturday, September 5, 2015 1:44 PM
>
> >> *To:* [email protected] < mailto: [email protected] > < mailto: [email protected] >
>
> >> *Subject:* [NMusers] Estimation of ke0 from raw data
> >>
> >> Hi,
> >>
> >> I have a data set containing PK concentrations and PD effect.
> >>
> >> When plotting PD as a function of PD a clear anti-clockwise hysteresis
> >>
> >> plot appears.
> >>
> >> I would like to get a (rough) estimate of the PD time delay w.r.t. the
> >> PK without
> >>
> >> using a compartmental description for the observed PK, even not using
> >>
> >> a polynomal function that fits the PK. The assumption I make is that
> >>
>
> >> all PD delay can be explained by the delay through an effect compartment.
>
> >>
> >> I am wondering if methods exist that solely use the raw data to
> >>
> >> calculate such time delays.
> >>
> >> Thank you for any comment/suggestion,
> >>
> >> Jos
> >>
> >> *Jos Lommerse*
> >>
> >> Modeler Consultant
> >>
> >> /Quantitative Solutions BV/
> >>
> >> /Molenweg 79/
> >>
> >> /5349 AC Oss/
> >>
> >> /The Netherlands/
> >>
>
> >> [email protected] < mailto: [email protected] > < mailto: [email protected] >
>
> >>
> >> +31 412 211102
> >>
> >> Notice: This e-mail message, together with any attachments, contains
> >> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>
> >> New Jersey, USA 07033), and/or its affiliates Direct contact information
>
> >> for affiliates is available at
>
> >> http://www.merck.com/contact/contacts.html ) < http://www.merck.com/contact/contacts.html%29 > that may be confidential, >> proprietary copyrighted and/or legally privileged. It is intended solely >> for the use of the individual or entity named on this message. If you are
>
> >> not the intended recipient, and have received this message in error,
> >> please notify us immediately by reply e-mail and then delete it from
> >> your system.
> >>
> >> *NOTICE: *The information contained in this electronic mail message is
> >> intended only for the personal and confidential use of the designated
> >> recipient(s) named above. This message may be an attorney-client
>
> >> communication, may be protected by the work product doctrine, and may be
>
> >> subject to a protective order. As such, this message is privileged and
> >> confidential. If the reader of this message is not the intended
> >> recipient or an agent responsible for delivering it to the intended
> >> recipient, you are hereby notified that you have received this message
>
> >> in error and that any review, dissemination, distribution, or copying of
>
> >> this message is strictly prohibited. If you have received this
> >> communication in error, please notify us immediately by telephone and
>
> >> e-mail and destroy any and all copies of this message in your possession
>
> >> (whether hard copies or electronically stored copies). Thank you.
> >>
> >>
> >> buSp9xeMeKEbrUze
> >>
> >> Notice: This e-mail message, together with any attachments, contains
> >> information of Merck & Co., Inc. (2000 Galloping Hill Road, Kenilworth,
>
> >> New Jersey, USA 07033), and/or its affiliates Direct contact information
>
> >> for affiliates is available at
>
> >> http://www.merck.com/contact/contacts.html ) < http://www.merck.com/contact/contacts.html%29 > that may be confidential, >> proprietary copyrighted and/or legally privileged. It is intended solely >> for the use of the individual or entity named on this message. If you are
>
> >> not the intended recipient, and have received this message in error,
> >> please notify us immediately by reply e-mail and then delete it from
> >> your system.
> >>
>
>