Colleagues
I have been troubled by a minor issue for some time. Consider the following
situation:
Dose is reported in mg salt
Cp is reported in ng/ml base
Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in
theory, dose should be converted to mg base (or concentration to ng/ml salt).
However, I am not sure if everyone does that.
In fact, an argument against it is that not doing the conversion permits one to
relate the administered dose (which is usually based on salt) to a Cp value
(usually based on base).
I am interested to hear what approach people use.
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone: 1-866-PLessThan (1-866-753-7784)
Fax: 1-866-PLessThan (1-866-753-7784)
www.PLessThan.com
Correcting for salt vs. base
Dear all,
As you say, to obtain the correct pharmacokinetic parameters, the mass of dose
and concentration should be related to the same entity, in this case the base.
This would correspond to using molar units for both dose and concentration.
I believe and hope most people are aware of this, and, the main rule is that
the strength in mg (mass unit) of a medicinal product given on the packages
refers to the base, not the salt, since different salts of the same substance
may be used. (however there are some exceptions for historical reasons).
All the best from Siv
--------------------------------------------------------------------------------------------------------------------------------------------------------------
Siv Jönsson, PhD
Researcher
Dept of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Sweden
http://www.farmbio.uu.se/research/researchgroups/pharmacometrics/
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Fisher Dennis
Sent: den 26 mars 2014 13:57
To: [email protected]
Subject: [NMusers] Correcting for salt vs. base
Colleagues
I have been troubled by a minor issue for some time. Consider the following
situation:
Dose is reported in mg salt
Cp is reported in ng/ml base
Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in
theory, dose should be converted to mg base (or concentration to ng/ml salt).
However, I am not sure if everyone does that.
In fact, an argument against it is that not doing the conversion permits one to
relate the administered dose (which is usually based on salt) to a Cp value
(usually based on base).
I am interested to hear what approach people use.
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone: 1-866-PLessThan (1-866-753-7784)
Fax: 1-866-PLessThan (1-866-753-7784)
http://www.plessthan.com/
Hi Dennis,
We typically convert the dose to mg-eq of the base and account for water of
hydration where appropriate (e.g. morphine sulfate pentahydrate).
Cheers... Brian
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Fisher Dennis
Sent: Wednesday, March 26, 2014 8:57 AM
To: [email protected]
Subject: [NMusers] Correcting for salt vs. base
Colleagues
I have been troubled by a minor issue for some time. Consider the following
situation:
Dose is reported in mg salt
Cp is reported in ng/ml base
Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in
theory, dose should be converted to mg base (or concentration to ng/ml salt).
However, I am not sure if everyone does that.
In fact, an argument against it is that not doing the conversion permits one to
relate the administered dose (which is usually based on salt) to a Cp value
(usually based on base).
I am interested to hear what approach people use.
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone: 1-866-PLessThan (1-866-753-7784)
Fax: 1-866-PLessThan (1-866-753-7784)
http://www.plessthan.com/
It depends on how the dose is reported, Dennis. In many cases salts are dosed using the quantity of based delivered. The clearest example is fosphenytoin, which is dosed in phenytoin equivalents, and the drug measured in plasma is phenytoin. However, if the dose delivered is reported as the amount of salt, then I would decrease the AMT by a multiplier S which should be a known constant.
Paul
Quoted reply history
On 3/26/2014 7:57 AM, Fisher Dennis wrote:
> Colleagues
>
> I have been troubled by a minor issue for some time. Consider the following situation:
>
> Dose is reported in mg salt
> Cp is reported in ng/ml base
>
> Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in theory, dose should be converted to mg base (or concentration to ng/ml salt).
>
> However, I am not sure if everyone does that.
>
> In fact, an argument against it is that not doing the conversion permits one to relate the administered dose (which is usually based on salt) to a Cp value (usually based on base).
>
> I am interested to hear what approach people use.
>
> Dennis
>
> Dennis Fisher MD
> P < (The "P Less Than" Company)
> Phone: 1-866-PLessThan (1-866-753-7784)
> Fax: 1-866-PLessThan (1-866-753-7784)
> www.PLessThan.com http://www.plessthan.com/
--
Paul R. Hutson, Pharm.D.
Professor
Senior Associate Dean for Academic Affairs
UW School of Pharmacy
T: 608.263.2496
F: 608.265.5421
Hi Dennis,
In my experience, most (but not all) doses are expressed as mg of free base,
eg, 0.5mg anagrelide (as 0.61mg of anagrelide*HCl). This facilitates changing
salt forms where the dose of free base may be unchanged while the dose of the
salt form will vary based on the size of the salt. I try to reinforce this
approach with my CMC colleagues whenever possible to ensure consistency.
However, I agree with you that calculation of clearance and volume should be
based on mg of the administered free-base in cases where the dose is expressed
as mg of the salt form.
Best regards,
Steve
Steven M. Troy
Clinical Pharmacology and Pharmacokinetics
Shire
725 Chesterbrook Boulevard
Wayne, PA 19087-5637
USA
Office: +1 (484) 595 8780
Mobile/Cell +1 (484) 375 3692
[email protected]<mailto:[email protected]>
http://www.shire.com
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Fisher Dennis
Sent: Wednesday, March 26, 2014 8:57 AM
To: [email protected]
Subject: [NMusers] Correcting for salt vs. base
Colleagues
I have been troubled by a minor issue for some time. Consider the following
situation:
Dose is reported in mg salt
Cp is reported in ng/ml base
Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in
theory, dose should be converted to mg base (or concentration to ng/ml salt).
However, I am not sure if everyone does that.
In fact, an argument against it is that not doing the conversion permits one to
relate the administered dose (which is usually based on salt) to a Cp value
(usually based on base).
I am interested to hear what approach people use.
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone: 1-866-PLessThan (1-866-753-7784)
Fax: 1-866-PLessThan (1-866-753-7784)
http://www.plessthan.com/
******************************************************
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in Jersey No. 99854
Registered Office: 22 Grenville Street, St Helier, Jersey JE4 8PX
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I prefer converting dose to the base. The advantages I see is that the resulting PK parameter values can be more correctly interpreted in the context of physiologic processes (hepatic blood flow, GFR, absolute bioavailability etc).
Edmund
At 05:57 AM 3/26/2014, Fisher Dennis wrote:
> Colleagues
>
> I have been troubled by a minor issue for some time. Consider the following situation:
>
> Dose is reported in mg salt
> Cp is reported in ng/ml base
>
> Since CL is dose / AUC and AUC is merely the integral of Cp vs. time, in theory, dose should be converted to mg base (or concentration to ng/ml salt).
>
> However, I am not sure if everyone does that.
>
> In fact, an argument against it is that not doing the conversion permits one to relate the administered dose (which is usually based on salt) to a Cp value (usually based on base).
>
> I am interested to hear what approach people use.
>
> Dennis
>
> Dennis Fisher MD
> P < (The "P Less Than" Company)
> Phone: 1-866-PLessThan (1-866-753-7784)
> Fax: 1-866-PLessThan (1-866-753-7784)
> http://www.plessthan.com/www.PLessThan.com
Edmund V. Capparelli, Pharm.D.
Professor of Clinical Pediatrics and Clinical Pharmacy
Director, Center for Research in Pediatric and Developmental Pharmacology (RPDP)
Pediatric Pharmacology and Drug Discovery
University of California, San Diego
858-246-0009 (telephone)
858-534-5611 (fax)
Perhaps I would state it stronger. I think if one were to use different units
for dose and concentration, the units (or parameter name) of clearance and
volume would need to be modified to acknowledge this fact. I actually cannot
recall ever having seem such modification.... anyone? Using different input
units (such as salt form for dose and free base for concentration) without
further annotation would be a bad practice if you ask me.
With a pharmacological and even pharmacokinetic perspective in mind I
personally would prefer to use molar concentrations over mass concentrations.
Molecules bind targets or enzymes, not mass. Unfortunately other forces are
driving towards the use of mass concentrations obviously. It cannot - or at
least should not - hurt to push back once in a while.
Best regards,
Jeroen
J. Elassaiss-Schaap Senior Principal Scientist
Phone: + 31 412 66 9320
MSD | PK, PD and Drug Metabolism | Clinical PK-PD Mail stop KR
4406 | PO Box 20, 5340 BH Oss, NL
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Capparelli, Edmund
Sent: Wednesday, March 26, 2014 17:46
To: Fisher Dennis; [email protected]
Subject: Re: [NMusers] Correcting for salt vs. base
I prefer converting dose to the base. The advantages I see is that
the resulting PK parameter values can be more correctly interpreted
in the context of physiologic processes (hepatic blood flow, GFR,
absolute bioavailability etc).
Edmund
At 05:57 AM 3/26/2014, Fisher Dennis wrote:
>Colleagues
>
>I have been troubled by a minor issue for some time. Consider the
>following situation:
> Dose is reported in mg salt
> Cp is reported in ng/ml base
>
>Since CL is dose / AUC and AUC is merely the integral of Cp vs.
>time, in theory, dose should be converted to mg base (or
>concentration to ng/ml salt).
>However, I am not sure if everyone does that.
>In fact, an argument against it is that not doing the conversion
>permits one to relate the administered dose (which is usually based
>on salt) to a Cp value (usually based on base).
>
>I am interested to hear what approach people use.
>
>Dennis
>
>Dennis Fisher MD
>P < (The "P Less Than" Company)
>Phone: 1-866-PLessThan (1-866-753-7784)
>Fax: 1-866-PLessThan (1-866-753-7784)
http://www.plessthan.com/www.PLessThan.com
>
>
Edmund V. Capparelli, Pharm.D.
Professor of Clinical Pediatrics and Clinical Pharmacy
Director, Center for Research in Pediatric and Developmental
Pharmacology (RPDP)
Pediatric Pharmacology and Drug Discovery
University of California, San Diego
858-246-0009 (telephone)
858-534-5611 (fax)
Notice: This e-mail message, together with any attachments, contains
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Hi Dennis,
Your main question is a straightforward one -- both the dose and concentration
should be expressed w/respect to the same entity. When the concentration is
expressed in terms of base (the norm), it makes sense to express the dose in
terms of base for PK analysis.
What is in the label is another issue. There is a guidance (web site given
below) from the FDA that says they will follow the USP Salt Policy which became
effective in May 1, 2013. That policy states that, for newly approved drugs,
"The strength also will be expressed in terms of the active moiety (e.g., "100
mg newdrug") rather than the salt strength equivalent (e.g., "123.7 mg newdrug
hydrochloride")."
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM379753.pdf
So, for paroxetine mesylate, which was approved July 2013, the package insert
says, 'BRISDELLE is available as 7.5 mg pink capsules printed with black edible
ink with “NOVEN” and “7.5 mg” on the capsule. Each capsule contains 9.69 mg
paroxetine mesylate equivalent to 7.5 mg paroxetine base.'
For mipomersen sodium, which was approved Jan 2013, the package insert says,
'Each vial or pre-filled string of KYNAMRO provides 200 mg of mipomersen
sodium…'
With this policy, it seems prudent to look at the package insert and check what
the dose amount refers to, salt or base, because there are exceptions (see
guidance) and you would have to know with certainty when the drug was approved
to make a determination.
Best regards,
Nancy
Nancy C Sambol, PharmD
Associate Clinical Professor
Dept of Bioengineering & Therapeutic Sciences
Schools of Pharmacy & Medicine
University of California San Francisco
San Francisco CA 94143-0912
415-476-8884
[email protected]