- On 23 Feb 2003 at 07:05:51, jagadeesh gouda (jaggagouda.at.yahoo.co.in) sent the message

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dear pharma pk friends

Can u give me equation for loading dose and

maintainance dose calculation for sustained release

solid dosageform from pharmacokinetics of drug .

jagadeesh t

Formulation development

Aristo pharma

MADHYAPRADESH

INDIA

[Lots of equation on my website at http://www.boomer.org/c/p1/ and

http://www.boomer.org/c/p3/ (and others) but what release/absorption

characteristic do you expect for the components of your sustained

release formulation..i.e fast first order with slow zero order or slow

and fast first order, e.g. - db] - On 27 Feb 2003 at 10:36:55, "Melethil, Srikumaran K." (melethils.at.umkc.edu) sent the message

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Dear Jagadeesh,

Assuming a one-compartment model and zero-order release:

LD = Vd *Cpss/F; where LD is the loading dose, Vd is the volume of

distribution and Cpss is the steady state concentration you wish to

maintain and F is the bioavailable fraction.

MD = (Cpss*Vd*k*T)/F where MD is the maintenance dose; k is the

overall elimination rate constant and T is the release time.

Hope this helps.

Srikumaran K. Melethil, Ph.D., J.D.

Professor Emeritus, Pharmaceutics

University of Missouri- Kansas City - On 28 Feb 2003 at 08:23:30, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message

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> Assuming a one-compartment model and zero-order release:

>

> LD = Vd *Cpss/F; where LD is the loading dose, Vd is the volume of

> distribution and Cpss is the steady state concentration you wish to

> maintain and F is the bioavailable fraction.

>

> MD = (Cpss*Vd*k*T)/F where MD is the maintenance dose; k is the

> overall elimination rate constant and T is the release time.

>

Algebraically OK but physiologically wrong. The average steady state

concentration and thus the maintenance dose rate is NOT affected by

volume of distribution. It is determined by clearance (CL):

MD = (Cpss*CL*T)/F

The point of this distinction is to emphasize that if you have factors

that affect volume of distribution e.g. altered body composition in

obesity, which do not affect elimination then the loading dose may

require adjustment but the maintenance dose rate does not need to

change.

Nick Holford, Divn Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 27 Feb 2003 at 12:24:51, ehab eldesoky (ehegypt.-at-.yahoo.com) sent the message

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The following message was posted to: PharmPK

Dr.Srikumaran K. Melethil,

In your reply, I would like please to clarify two

point:

T= release time. do you mean dose interval?

cpss= what concentration we select for the equation.

Is it average or trough steady state concentration?.

Thank You

Ehab EL Desoky M.D.

Assiut University. Egypt - On 27 Feb 2003 at 16:30:28, "Melethil, Srikumaran K." (melethils.-a-.umkc.edu) sent the message

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Dear Dr. Desoky,

No, T is not the dosing interval; T is time over which you want the

drug to be released at the site (e.g., 12 hr, 8 hr etc). If the dosing

interval and T are equal, then it mimics continuous infusion. In that

case, there is no peak or trough; it can be used as an average, when T

and the dosing interval are not the same.

Srikumaran K. Melethil, Ph.D., JD

Professor Emeritus, Pharmaceutics

School of Pharmacy

University of Missouri- Kansas City - On 28 Feb 2003 at 12:45:32, Nick Holford (n.holford.at.auckland.ac.nz) sent the message

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"Melethil, Srikumaran K." wrote:

>

> No, T is not the dosing interval; T is time over which you want the

> drug to be released at the site (e.g., 12 hr, 8 hr etc). If the dosing

> interval and T are equal, then it mimics continuous infusion. In that

> case, there is no peak or trough; it can be used as an average, when T

> and the dosing interval are not the same.

The original model proposed by Prof Melethil was

> MD = (Cpss*Vd*k*T)/F where MD is the maintenance dose; k is the

> overall elimination rate constant and T is the release time.

The usual interpretation of Cpss in this context is that it means the

average steady state concentration. In that case the maintenance dose T

must be interpreted as the dosing interval. The time course of release

of the formulation makes no difference because the average

concentration reflects the integral of conc over time and thus time is

not relevant.

Rate In = Rate Out ; mass balance basis for this model

MDR = CL/F * CPssavg ; maintenance dose rate for target of

CPssavg

MD = MDR * Dosing Interval ; intermittent maintenance dose with

regular dosing

IMHO there is no simple interpretation of what Cpss means if T is the

release time of the formulation and T is not equal to the dosing

interval. Perhaps Prof Melethil would enlighten us?

Nick

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

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