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RE: Correcting for salt vs. base

From: Troy, Steven <stroy>
Date: Wed, 26 Mar 2014 14:29:08 +0000

Dennis,

Thank you for the correction. I understand your point that the practical =
approach would be to use the labeled dose as the clearance relates the dos=
e to exposure, and it is simpler to use the labeled dose without continual=
ly correcting from mg of the salt to mg of the free base. In this case, t=
he correction from weight of the salt to weight of the free base is captur=
ed in the bioavailability term F when clearance is expressed as CL/F. I t=
hink either approach can be acceptable provided you explain whether cleara=
nce is calculated based on the mg of free base or the 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
stroy
www.shire.com<http://www.shire.com>
From: Fisher Dennis [mailto:fisher
Sent: Wednesday, March 26, 2014 10:20 AM
To: Troy, Steven
Cc: nmusers
Subject: Re: [NMusers] Correcting for salt vs. base

Troy

You wrote:
            I agree with you that calculation of clearance and volume shou=
ld be based on mg of the administered free-base in cases where the dose is=
 expressed as mg of the salt form.

I am not sure that I advocated either position. You argue for the positio=
n that is theoretically correct. But, the alternative is more "practical"=
. The obvious solution is to reference all doses and concentrations to th=
e same material (either salt or base but base makes more sense). But, as =
I noted in a reply to Siv, a recent FDA approval identified the dose in te=
rms of salt.

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/>



On Mar 26, 2014, at 7:14 AM, Troy, Steven <stroy
ire.com>> wrote:


Hi Dennis,

In my experience, most (but not all) doses are expressed as mg of free bas=
e, eg, 0.5mg anagrelide (as 0.61mg of anagrelide*HCl). This facilitates c=
hanging 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 r=
einforce 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
stroy
www.shire.com<http://www.shire.com/>
From: owner-nmusers
ailto:owner-nmusers
Sent: Wednesday, March 26, 2014 8:57 AM
To: nmusers
Subject: [NMusers] Correcting for salt vs. base

Colleagues

I have been troubled by a minor issue for some time. Consider the followi=
ng 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 t=
heory, 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 o=
ne to relate the administered dose (which is usually based on salt) to a C=
p 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/>




******************************************************
Shire plc, the ultimate parent of the Shire Group of companies, is registe=
red in Jersey No. 99854
Registered Office: 22 Grenville Street, St Helier, Jersey JE4 8PX
******************************************************


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******************************************************
Shire plc, the ultimate parent of the Shire Group of companies, is registe=
red in Jersey No. 99854
Registered Office: 22 Grenville Street, St Helier, Jersey JE4 8PX
******************************************************


Please consider the environment before printing this e-mail

This email and any files transmitted with it are confidential and
may be legally privileged and are intended solely for the use of
the individual or entity to whom they are addressed. If you are
not the intended recipient please note that any disclosure,
distribution, or copying of this email is strictly prohibited and may
be unlawful. If received in error, please delete this email and any
attachments and confirm this to the sender.
Received on Wed Mar 26 2014 - 10:29:08 EDT

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