- On 6 Nov 2001 at 10:07:53, "Bonate, Peter" (pbonate.-at-.ilexonc.com) sent the message

Back to the Top

The following message was posted to: PharmPK

I have a question to the group. Here is a calculation given to me by

someone else.

At the 15 mg dose to healthy volunteers the peak plasma level

was 1.5 ug/ml.

Blood volume in humans is 70 ml/kg which in a 70 kg person

translates into 4900 mls of whole blood or 2940 mls of plasma.

Therefore, 2940 mls x 1.5 ug/ml = 4410 ug of drug in the plasma

compartment.

4.41 mg/ 15 mg dose ==> at least 29.4 % of the drug is orally

bioavailable

Does this make sense to you?

Thanks.

Peter L. Bonate, PhD

Director, Pharmacokinetics/Pharmacodynamics

ILEX Oncology

4545 Horizon Hills Blvd.

San Antonio, Tx 78229

phone: 210-949-8662

fax: 210-949-8487

email: pbonate.at.ilexonc.com - On 6 Nov 2001 at 22:38:18, David_Bourne (david.-a-.boomer.org) sent the message

Back to the Top

[Quite a few answers, interesting calculation - could be useful for

low Vd drugs ;-) - db]

From: Varun_Garg.aaa.vpharm.com

Date: Tue, 6 Nov 2001 12:53:27 -0500

To: david.at.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

I think it makes sense, although it would be most useful for estimating

the minimum bioavailability of drugs that are not highly bound to tissues

and highly bound to plasma proteins.

I checked the F of Indocyanin Green, which is almost completely restricted

to plasma and administered by IV .

After a dose of 0.5 mg/kg, the mean Cmax obtained in serum was 7.2 ug/mL

and the back-extrapolated mean C0 = 13.4 ug/mL.

Using a plasam volume of 2940 mL (the mean weight of subjects was 70.08

kg), this would yield the amount in plasma = 13.4*2940 = 39.4 mg.

F= 39.4/35, so about right for an IV drug.

Varun

Varun Garg, Ph.D.

Vertex Pharmaceuticals, Inc.

130 Waverly Street

Cambridge, MA 02139

---

From: pradeepbhadauria.-at-.sify.com

Date: Tue, 06 Nov 2001 23:21:49 +0600 (IST)

To: david.aaa.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Dear Dr. Bonate,

As per the classical definition of bioavailability it is the rate and

extent to which it reaches into systemic circulation from the site of

action. Basis of your calculation is not correct in my opinion

because what you have calculated is plasma drug concentration at that

time point of assessment.i.e at Cmax.considering one compartment

model of prediction . Even if you want to calculate the extent of

absorption ( amount reaches in circulation after oral adminstration

i.e. AUC ) you need of have more than one points( Preferably 4-5

points) to calculate the AUC( t =0-infinity) with accuracy.

Any further discussion in said matter will be appreciated.

With best regards,

Pradeep S. Bhadauria

R&D Executive,

Dr. Reddy's Laboratories Limited.

Hyderabad. ( INDIA ).

---

From: Spiresgate.aaa.aol.com

Date: Tue, 6 Nov 2001 14:52:32 EST

To: david.aaa.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

Dear Peter

It makes sense to me.

Most people assume when quoting plasma concentrations that the plasma

sample is representative of the total plasma in the body. therefore

there must be 4.41 mg of the drug in the systemic circulation, hence

the quoted bioavailability (or rather the total absorbed). the key

to the question perhaps is that this is a minimum - it can't be less

than this, but it could be (and probably is) more.

Joe Chamberlain

Spiresgate.-a-.aol.com

---

From: Norma Rohde

Date: Wed, 7 Nov 2001 07:48:01 +1100

To: david.at.boomer.org

Subject: RE: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Peter,

Seems to me there are three underlying assumptions of your calculation -

tissue distribution of the drug is negligible

the drug is totally absorbed into the systemic circulation at the

measurement timepoint

excretion or metabolism of the drug is negligible up to the time

point of the measurement

There would not be too many drugs that could comply with all these criteria.

Your estimate of bioavailability would definitely be 'at least' but even as

a rough guide could be quite misleading if one or more of the assumptions

aren't true.

Norma Rohde

---

From: hmehler.aaa.mehler.com

Date: Tue, 6 Nov 2001 11:12:31 -0800

To: david.-at-.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Dr. Bonate:

We should be careful not to confuse the terms "bioavailability" and

"percent of drug absorbed". Bioavailability generally refers to a ratio of

areas under the curve obtained for the same compound administered by oral

and intravenous routes of administration. Your calculation seems to be an

attempt to quantify the percent of an orally administered drug absorbed into

the circulation.

What is the hypothetical volume of distribution of the drug and what

is tmax? Is the drug concentrated in peripheral tissue(s) at a

concentration greater than that of plasma (or whole blood)? If this is the

case would your calculation be biased?

Sincerely,

Howard Mehler

Howard S Mehler PhD JD & Associates Inc

---

From: hmehler.at.mehler.com

Date: Tue, 6 Nov 2001 17:38:18 -0800

To: david.-at-.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Dr. Bonate:

To follow up to my previous email, here is a simple equation which

demonstrates the relationship between Cmax, F and V.

F x Dose

Cmax = __________

V

This can be found in Pharmacokinetics and Pharmacodynamic Data Analysis (ed

Gabrielson and Weiner) page 335.

Sincerely,

Howard S Mehler

Howard S Mehler PhD JD & Associates Inc

hmehler.-at-.mehler.com

---

From: "Melethil, Srikumaran K."

Date: Tue, 6 Nov 2001 12:41:50 -0600

To: david.at.boomer.org

Subject: RE: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Dear Peter:

Interesting question.

Conceptually, (assuming rapid, homogeneous mixing as with the one

compartment model) the answer makes sense.

Mathematically (one compartment) , [Cp(max) * (Vd)/D)] = F*

[ka/(ka-ke)] * (exp(-ktmax- exp (-katmax).

It would be interesting to know how the computed values by the two

methods compare. I look forward to comments by others

Sri

Srikumaran K. Melethil, Ph.D., JD (2001)

Professor, Pharmaceutics and Medicine

University of Missouri- Kansas City

203B Katz Hall (School of Pharmacy)

Kansas City, MO 64110

Phone: voice- 816-235-1794; fax - 816-235-5190 - On 7 Nov 2001 at 14:43:17, David Bourne (david.aaa.boomer.org) sent the message

Back to the Top

[A few more replies - remember Dr Bonate was suggesting/asking about

this as an approximate method for a 'minimum' value for the amount

absorbed - db]

From: "arief hakim"

Date: Tue, 06 Nov 2001 21:24:44 -0800

To: david.at.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

If we want to know how much drug in the body we can use this :

Db = Cp*Vd

and F = Dose*100/Db

---

From: JYOTI PALIWAL

Date: Wed, 7 Nov 2001 13:12:53 +0530

To: david.-a-.boomer.org

Subject: RE: PharmPK Re: Bioavailability based on single time point

The following message was posted to: PharmPK

It makes lot of sense and application to compounds in early preclinical

discovery/development phase where iv data is not available.

As an extension to this concept, if one has 3 to 4 plasma concentrations of

a compound (with linear one compartment kinetics)at terminal log-linear

phase, then concentration at time (Cp0)can be obtained by extrapolation to

zero or linear regression. Further by applying Dr. Bonate's logic, one can

get a close estimate of oral bioavailability.

I look forward to share the opinion and experience of the group.

Jyoti Paliwal, Ph.D.

Ranbaxy Research Laboratories

Gurgaon-122001 (India)

---

From: "Hans Proost"

Date: Wed, 7 Nov 2001 12:02:14 MET

To: david.at.boomer.org

Subject: Re: PharmPK Re: Bioavailability based on single time point

The following message was posted to: PharmPK

Dr. Howard Mehler wrote:

> We should be careful not to confuse the terms "bioavailability" and

> "percent of drug absorbed". Bioavailability generally refers to a ratio of

> areas under the curve obtained for the same compound administered by oral

> and intravenous routes of administration. Your calculation seems to be an

> attempt to quantify the percent of an orally administered drug absorbed into

> the circulation.

This is a strange reasoning. By definition, bioavailability refers to

the fraction of the dose reaching the general circulation. And

bioavailability may be assessed from the ratio of AUC's after an

extravascular and intravenous dose, implicitly assuming that

clearance is the same on both occasions.

> To follow up to my previous email, here is a simple equation which

> demonstrates the relationship between Cmax, F and V.

>

> F x Dose

> Cmax = __________

> V

>

> This can be found in Pharmacokinetics and Pharmacodynamic Data Analysis (ed

> Gabrielson and Weiner) page 335.

This is a strange equation, since it would follow that no elimination

occurs before Cmax is reached, and that distribution occurs

instantaneously. This is never true, so this equation is never

correct. Of course it can be used as a rough approximation, in

particular if elimination is slow, distribution is fast and absorption is

fast.

Dr. Bonate's equation is 'better', since it claims to calculate a

minimum value for F, and this seems correct.

best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.-a-.farm.rug.nl

---

From: "Paul S. Collier"

Date: Wed, 07 Nov 2001 13:08:11 +0100

To: david.at.boomer.org

Subject: Re: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

The method for calculation of bioavailability described by someone in

coversation with Dr Bonate is based on 4 assumptions, one or more of

which would almost certainly be untrue for all drugs. These assumptions

are as follows:

1. assumes absorption is complete at the time of the peak plasma

concentration (not true where absorption of the drug obeys first order

kinetics)

2. assumes no elimination prior to achieving and measuring the peak

plasma concentration (I cannot think of a situation where that could be

the case - if it was true, it would make estimation of apparent volumes

of distribution much easier)

3. assumes the drug does not distribute outside of the blood (not many

examples spring to mind)

4. assumes that plasma concentration and blood concentrations are

identical (unlikely to be the case if the drug binds to plasma proteins)

---

From: "Tata, Prasad N"

Date: Wed, 7 Nov 2001 08:17:47 -0600

To: david.at.boomer.org

Subject: RE: PharmPK Bioavailability based on single time point

The following message was posted to: PharmPK

Dear Peter:

I am assuming that you considered hematocrit as 40, which is a conservative

estimate. Other consideration could be 9% body weight for interstitial

fluids (extracellular water including plasma, assuming that there is no

tissue binding by your drug F= 70000*0.09*1.5/15000=0.63. Therefore fraction

of dose absorbed would be 63%. Hope this reasoning helps.

Prasad Tata

Mallinckrodt, Inc.

St. Louis, MO.

---

From: Edmond Edwards

Date: Wed, 7 Nov 2001 09:23:30 -0500

To: david.at.boomer.org

Subject: RE: PharmPK Bioavailability based on single time point

Just some questions:

If there's only one point, how can you be sure it's Cmax? If there's

more than one point (presumably) why not use this information?

Just asking.

... Edmond - On 9 Nov 2001 at 12:55:39, hmehler.aaa.mehler.com sent the message

Back to the Top

The following message was posted to: PharmPK

To All Interested Participants:

In response to Dr. Proost's comments, for the record it should be noted

that 21 CFR Section 320.1 (a) provides the following definition of

bioavailability:

"Bioavailability means the rate and extent to which the

active ingredient . . . is absorbed from a drug product....

The fraction or percent of drug absorbed indicates the extent of

absorption however 'F' does not provide information on the rate of

absorption and cannot suffice as a measure of bioavailability.

The intuitive equation Cmax = F x D / V was offered to demonstrate the

direct proportionality between the fraction of dose absorbed and the volume

of distribution. For a given Cmax and D, underestimation of the volume of

distribution will cause an underestimation of F the fraction of drug

absorbed. In fact, if you rearrange the equation in terms of F = Cmax x V /

D you have

Dr. Bonate's exact method of calculation ( where V is constrained to the

volume of the plasma compartment).

Sincerely,

Howard S Mehler

Howard S Mehler PhD JD & Associates Inc

hmehler.aaa.mehler.com - On 11 Nov 2001 at 21:32:08, Walt Woltosz (walt.at.simulations-plus.com) sent the message

Back to the Top

The following message was posted to: PharmPK Howard Mehler wrote:

>To All Interested Participants:

> In response to Dr. Proost's comments, for the record it should be noted

>that 21 CFR Section 320.1 (a) provides the following definition of

>bioavailability:

>

> "Bioavailability means the rate and extent to which the

>active ingredient . . . is absorbed from a drug product....

>

> The fraction or percent of drug absorbed indicates the extent of

>absorption however 'F' does not provide information on the rate of

>absorption and cannot suffice as a measure of bioavailability.

>

Mehler has deleted a key phrase at the end of the 21 CFR 320.1

definition. The complete definition is:

"Sec. 320.1 Definitions. (a) Bioavailability means the rate and

extent to which the active ingredient or active moiety is absorbed

from a drug product and becomes available at the site of action. For

drug products that are not intended to be absorbed into the

bloodstream, bioavailability may be assessed by measurements intended

to reflect the rate and extent to which the active ingredient or

active moiety becomes available at the site of action."

The phrase "and becomes available at the site of action" is the key.

By definition, F *is* bioavailability. Fa is fraction absorbed.

F does provide information on the minimum extent of absorption,

because F >= Fa.

The difference between bioavailability (F) and fraction absorbed (Fa)

is the loss of drug after it is absorbed but before it reaches the

central circulation. The primary loss mechanisms are gut metabolism

and hepatic metabolism.

The most common usage is to define first pass extraction as the

amount of loss of drug that makes F different from Fa. Thus,

F = Fa (1 - FPE)

Walt Woltosz

Chairman & CEO

Simulations Plus, Inc. (SIMU)

1220 W. Avenue J

Lancaster, CA 93534-2902

U.S.A.

http://www.simulations-plus.com

Phone: (661) 723-7723

FAX: (661) 723-5524

E-mail: walt.-a-.simulations-plus.com - On 12 Nov 2001 at 14:04:38, Walt Woltosz (walt.aaa.simulations-plus.com) sent the message

Back to the Top

The following message was posted to: PharmPK

>F does provide information on the minimum extent of absorption,

>because F >= Fa.

>

Can I blame this on jet lag - just got back from Japan when I wrote

this. Clearly,

Fa >= F

Walt Woltosz

Chairman & CEO

Simulations Plus, Inc. (SIMU)

1220 W. Avenue J

Lancaster, CA 93534-2902

U.S.A.

http://www.simulations-plus.com

Phone: (661) 723-7723

FAX: (661) 723-5524

E-mail: walt.aaa.simulations-plus.com - On 15 Nov 2001 at 13:04:38, hmehler.aaa.mehler.com sent the message

Back to the Top

The following message was posted to: PharmPK

If F is bioavailability then

Cl iv

F = _____________

Cl oral

which may be obtained from the ratio of dose corrected total areas under

the plasma concentration curves following oral and intravenous

administration of the same drug in the same subject, on different occasions.

Note that the foregoing equation differs significantly from the

equation [F= (C x V)/D] which began this discussion.

Sincerely,

Howard S Mehler

Howard S Mehler PhD JD & Associates Inc

hmehler.-a-.mehler.com - On 20 Nov 2001 at 10:35:38, David Bourne (david.-a-.boomer.org) sent the message

Back to the Top

[Two more replies - sorry for the delay - the PharmPK archive is now

up-to-date as of the last weekend (http://www.boomer.org/pkin/) - db]

From: Walt Woltosz

Date: Thu, 15 Nov 2001 12:54:30 -0800

To: david.at.boomer.org

Subject: Re: PharmPK Re: Bioavailability based on single time point

The following message was posted to: PharmPK At 01:04 PM 11/15/01

-0600, you wrote:

>PharmPK - Discussions about Pharmacokinetics

>Pharmacodynamics and related topics

>

>The following message was posted to: PharmPK

>

> If F is bioavailability then

>

> Cl iv

> F = _____________

>

> Cl oral

>

>which may be obtained from the ratio of dose corrected total areas under

>the plasma concentration curves following oral and intravenous

>administration of the same drug in the same subject, on different occasions.

>

This equation is based on the assumption that CL is independent of

concentration. This is close enough to reality for many compounds,

but not generalizable to all compounds. For example, for any drug

that undergoes concentration-dependent metabolism (Michaelis-Menten

kinetics), this will not be true

> Note that the foregoing equation differs significantly from the

>equation [F= (C x V)/D] which began this discussion.

>

Actually, what began this discussion was Peter Bonate's question about whether

[F >= (Cmax x Vplasma)/D], not

[F = (C x V)/D]

He did not use the equations, but this is what it amounts to.

The original post by Peter Bonate asked about an indication of

*minimum* bioavailability. The maximum concentration in plasma

multiplied by the plasma volume certainly gives a good estimate of

the amount of drug in in plasma at that time. So, although there may

be more drug in other tissues, there is at least this amount that

made it into the central circulation - the basis for calculating

bioavailability.

I believe that is all Peter was trying to find out, and I think it is

reasonable that bioavailability must be at least this amount.

Walt Woltosz

Chairman & CEO

Simulations Plus, Inc. (SIMU)

1220 W. Avenue J

Lancaster, CA 93534-2902

U.S.A.

http://www.simulations-plus.com

Phone: (661) 723-7723

FAX: (661) 723-5524

E-mail: walt.-at-.simulations-plus.com

---

From: "Hans Proost"

Date: Fri, 16 Nov 2001 13:55:16 MET

To: david.aaa.boomer.org

Subject: Re: PharmPK Re: Bioavailability based on single time point

The following message was posted to: PharmPK

Dear Dr. Mehler,

You wrote:

> If F is bioavailability then

>

> Cl iv

> F = _____________

>

> Cl oral

>

> which may be obtained from the ratio of dose corrected total areas under

> the plasma concentration curves following oral and intravenous

> administration of the same drug in the same subject, on different occasions.

This equation including the explanation is correct, but the equation

by itself is misleading. The assessment of F from the dose-corrected

AUC ratio implicitly assumes that clearance on both occasions is the

same.

I strongly advice never using the term Cl_oral for the term CL/F, as

in your equation (and many literature sources as well).

Best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.-a-.farm.rug.nl - On 26 Nov 2001 at 13:32:17, Balaji Agoram (Balaji.aaa.simulations-plus.com) sent the message

Back to the Top

"Bioavailability means the rate and extent to which the active

ingredient or active moiety is absorbed from a drug product and

becomes available at the site of action." so what we calculate either

using the AUC method or by direct measurement is a "systemic

availability" (lets call it Fs) - which we assume to be a measure of

the true bioavailability (Fb).

Dr. Mehler is correct in that the direct measurement of Fb as the

fraction reaching the systemic circulation does not address the

"rate" part of the definition of Fb. but the AUC method of Fb

calculation does. *for a given clearance* the AUC will be higher when

the rate of systemic appearance of the drug will be higher.

therefore, the calculated F will also be higher. but the AUC method

of Fb measurement has its own limitations e.g. when drug clearance is

nonlinear. also, the AUC method of Fb calculation assumes that rate

and extent of absorption go hand in hand. we at Simulations Plus are

in the process of preparing a short manuscript which shows that it is

possible for the AUC to increase while the fraction of drug reaching

the systemic circulation decreases! in that case, should the

calculated Fb be higher or lower?

therefore, we decided to stick to the definition of Fb as the

"fraction reaching the systemic circulation"(Fb=Fraction absorbed

(1-first pass)). the "rate" part of the definition seems fairly

ambiguous - it does not specify what rate of absorption should be

considered the minimum or the maximum or some sort of a time-averaged

rate, etc. on the other hand, the "fraction reaching the systemic

circulation" is a cold hard number. it is hard to estimate from

experiments, but in our simulations using GastroPlus, it can be

calculated directly.

The Cmax method of F estimation is a simplified version of the AUC

method, subject to assumptions such as no distribution, no

elimination until Cmax, etc. so, it is a good estimate of the minimum

F.

maybe it is a good time for these definitions to be re-evaluated and

standardized with the new flood of information available on each of

these processes. for e.g. with the recognition of gut first pass,

absorption is being redefined as the fraction crossing the apical

intestinal barrier and distinct from the fraction reaching systemic

circulation.

Balaji Agoram, Ph.D.

Senior Scientist/Product Manager

Simulations Plus, Inc. California

http://www.simulations-plus.com - On 27 Nov 2001 at 12:58:33, "Hans Proost" (J.H.Proost.-at-.farm.rug.nl) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Dr. Agoram,

Your comments with respect to the meaning of bioavailability are

correct (differentiating between 'systemic availability' and

'bioavailability'), although I am not quite sure that everybody uses

the same definition. This could start a new thread in the PharmPK

group!

You wrote also:

> Dr. Mehler is correct in that the direct measurement of Fb as the

> fraction reaching the systemic circulation does not address the

> "rate" part of the definition of Fb. but the AUC method of Fb

> calculation does. *for a given clearance* the AUC will be higher when

> the rate of systemic appearance of the drug will be higher.

This is not true. In case of linear kinetics, AUC is independent of the

rate of entering the systemic circulation, and thus are F (either Fs

or Fb). Of course, if kinetics are nonlinear, or if AUC is truncated

due to lack of sensitivity of the assay, then this could be the case.

But not as the general case.

> also, the AUC method of Fb calculation assumes that rate

> and extent of absorption go hand in hand.

Again, I do not agree. In principle, rate and extent of absorption are

independent. Of course, there may be many situations where this is

not the case (e.g. retarded release may result in decreased F), but

this is not the general case.

> we at Simulations Plus are

> in the process of preparing a short manuscript which shows that it is

> possible for the AUC to increase while the fraction of drug reaching

> the systemic circulation decreases! in that case, should the

> calculated Fb be higher or lower?

This sounds interesting! I am eager to read this paper.

> Fb ... is hard to estimate from experiments,

I still think that the AUC ratio is OK, perhaps with exception of some

rather strange cases.

> but in our simulations using GastroPlus, it can be

> calculated directly.

This can be the start for again a new thread: do you prefer

calculated values for F over values obtained from experimental AUC

values? I don't.

> maybe it is a good time for these definitions to be re-evaluated and

> standardized with the new flood of information available on each of

> these processes. for e.g. with the recognition of gut first pass,

> absorption is being redefined as the fraction crossing the apical

> intestinal barrier and distinct from the fraction reaching systemic

> circulation.

I agree. However, the problem is that we do not have easy access to

the experimental data needed to do this. Certainly not in humans.

Best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.-at-.farm.rug.nl - On 27 Nov 2001 at 15:12:57, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message

Back to the Top

The following message was posted to: PharmPK

"Balaji Agoram (by way of David Bourne)" wrote:

>

> PharmPK - Discussions about Pharmacokinetics

> Pharmacodynamics and related topics

>

> "Bioavailability means the rate and extent to which the active

> ingredient or active moiety is absorbed from a drug product and

> becomes available at the site of action." so what we calculate either

> using the AUC method or by direct measurement is a "systemic

> availability" (lets call it Fs) - which we assume to be a measure of

> the true bioavailability (Fb).

>

> Dr. Mehler is correct in that the direct measurement of Fb as the

> fraction reaching the systemic circulation does not address the

> "rate" part of the definition of Fb. but the AUC method of Fb

> calculation does. *for a given clearance* the AUC will be higher when

> the rate of systemic appearance of the drug will be higher.

I do not agree with the last statement. If clearance is constant i.e.

we assume first order kinetics then AUC, the integral of

concentration with respect to time, loses all information about time

and thus there can be no information about rate of absorption. This

is a fundamental problem with any method that computes AUC -- time is

lost.

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)373-7599x6730 fax:373-7556

http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm - On 28 Nov 2001 at 13:04:42, "Peter W. Mullen" (pmullen.aaa.kemic.com) sent the message

Back to the Top

The following message was posted to: PharmPK

"Balaji Agoram (by way of David Bourne)" wrote:

>

> PharmPK - Discussions about Pharmacokinetics

> Pharmacodynamics and related topics

>

> "Bioavailability means the rate and extent to which the active

> ingredient or active moiety is absorbed from a drug product and

> becomes available at the site of action." so what we calculate either

> using the AUC method or by direct measurement is a "systemic

> availability" (lets call it Fs) - which we assume to be a measure of

> the true bioavailability (Fb).

>

> Dr. Mehler is correct in that the direct measurement of Fb as the

> fraction reaching the systemic circulation does not address the

> "rate" part of the definition of Fb. but the AUC method of Fb

> calculation does. *for a given clearance* the AUC will be higher when

> the rate of systemic appearance of the drug will be higher.

If the kinetics are linear, AUC should NOT depend on the rate of systemic

appearance of drug. AUC is truly independent of the underlying measure of

absorption rate, namely, Ka, in one or multi- compartment models. See

Phillips, K., Biopharmaceutics and Drug Disposition 14, 643 (1993) and Zha,

J. et al., Drug Information J. 29, 989 (1995).

For the record, concerning the distinction between "absorption" and

"bioavailability" as mentioned previously in this thread, a recent

commentary by Win Chiou attempts to clarify the issue (He recommends using

"bioavailability" in all instances.) and also invites others to contribute

their opinions on the matter. (See: Chiou, W., J. Pharmacokin. and

Pharmacodyn. 28, 3 (2001))

Also, since an ideal metric for rate in bioavailability/bioequivalence

studies is problematic (especially, Cmax), I note that the latest FDA

Guidance now emphasizes thinking in terms of "exposure" rather than "rate

and extent" in such studies.

Best wishes,

Peter

Peter W. Mullen, Ph.D., FCSFS,

Kemic Bioresearch

PO Box 878

Kentville

Nova Scotia, B4N 4H8

Canada

Tel. 902-678-8195 Fax 902-678-2839 URL www.kemic.com - On 29 Nov 2001 at 10:52:32, Balaji Agoram (Balaji.-a-.simulations-plus.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Sir,

At 12:58 PM 11/27/01 -0600, you wrote:

>PharmPK - Discussions about Pharmacokinetics

>Pharmacodynamics and related topics

>

>The following message was posted to: PharmPK

>

>Dear Dr. Agoram,

>

>You wrote also:

>> Dr. Mehler is correct in that the direct measurement of Fb as the

>> fraction reaching the systemic circulation does not address the

>> "rate" part of the definition of Fb. but the AUC method of Fb

>> calculation does. *for a given clearance* the AUC will be higher when

>> the rate of systemic appearance of the drug will be higher.

>

>This is not true. In case of linear kinetics, AUC is independent of the

>rate of entering the systemic circulation, and thus are F (either Fs

>or Fb). Of course, if kinetics are nonlinear, or if AUC is truncated

>due to lack of sensitivity of the assay, then this could be the case.

>But not as the general case.

let us consider a drug, whose fraction absorbed when administered

orally is limited by dissolution. consider two doses of this drug -

dose 1 is made up of smaller particles than dose 2. since the drug is

dissolution limited, it is possible for a higher fraction of dose 1

to be absorbed than dose 2. if the clearance is the same for both

doses and is linear, the "rate of entering the systemic circulation"

of drug from dose 1 will be higher than from dose 2, and so will be

the AUC. i should probably rephrase my original comment as "*for a

given clearance* the AUC will be *equal to or higher* when the rate

of systemic appearance of the drug from an oral dose is higher".

it is true that the in the case that the same amount of drug made it

into systemic circulation the AUC is independent of the rate of

entering systemic circulation. for IV administration, this is true.

for oral administration this may not always be so.

>> Fb ... is hard to estimate from experiments,

>

>I still think that the AUC ratio is OK, perhaps with exception of some

>rather strange cases.

>

>> but in our simulations using GastroPlus, it can be

>> calculated directly.

>

>This can be the start for again a new thread: do you prefer

>calculated values for F over values obtained from experimental AUC

>values? I don't.

i do not suggest that calculated values be used exclusively over the

experimental AUC values. very few have the luxury of calculated F

values from sophisticated modelling programs or extensive

experiments. but it is imperative that people who use experimental

AUC values are aware of the pitfalls in its use. on the other hand,

it is important for modelers to understand experimental limitations.

as far as preference goes, if all i need is an idea of the

bioavailability, then the AUC method will suffice. but the simulated

F also gives me information on the reasons behind low (or high)

bioavailability, thus giving me valuable insight into the behavior of

the drug.

Balaji Agoram, Ph.D.

Senior Scientist/Product Manager

Simulations Plus, Inc. California

http://www.simulations-plus.com - On 3 Dec 2001 at 14:25:30, "Hans Proost" (J.H.Proost.-at-.farm.rug.nl) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Dr. Agoram,

Thank you for your reply. You wrote:

> let us consider a drug, whose fraction absorbed when administered

> orally is limited by dissolution. consider two doses of this drug -

> dose 1 is made up of smaller particles than dose 2. since the drug is

> dissolution limited, it is possible for a higher fraction of dose 1

> to be absorbed than dose 2.

OK. But this implies a nonlinear process, i.e. the rate of dissolution

is not proportional to the dose. And if the time for dissolution is not

limited due to movement away from absorption sites, the fraction

reaching the general circulation will be the same. You are right to

say 'it is possible', but F also may be the same (which is the 'normal

case' in my view).

> i should probably rephrase my original comment as "*for a

> given clearance* the AUC will be *equal to or higher* when the rate

> of systemic appearance of the drug from an oral dose is higher".

I still not agree. As stated before, in the 'normal case' AUC is

unaffected. You may say: ...the AUC may be higher ... due to an

increased fraction of the dose reaching the general circulation. (and

that was the point of discussion).

> if all i need is an idea of the

> bioavailability, then the AUC method will suffice.

'An idea of the bioavailability' is an understatement of the importance

of bioavailability for the relationship between dose and plasma

concentration. You simply need to know it, and the AUC method is

the most straightforward method to get it. In addition, AUC is a direct

measure of exposure to the drug, which is also a useful concept,

both for single-dose as well as for multi-dose drug use.

For the remainder, I agree with your view.

Best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.aaa.farm.rug.nl - On 20 Dec 2001 at 12:26:25, jakir pinjari (jakirpinjari.-a-.yahoo.com) sent the message

Back to the Top

As far as drug absorption is concern, it is very important in early

phase of drug discovery, more specific is before lead selection to

have an idea of absorption of NCE.So what I feel that if we are

geting the idea of its absorption from single point BA, we can

roughly predict the BA of that entity.Which will increase the speed

in discovery.In CaCO2 cell lines we are measuring the absorption of

drug and not the BA.So I think this single point BA will be useful

for getting a rough idea regarding absorption.Any way in single point

how we come to know about tmax ?For that we have to perform full

experiment.

With regards.

Jakir Pinjari.

Zydus Research Centre-Ahemadabad.

Want to post a follow-up message on this topic? If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Bioavailability based on single time point" as the subject

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)