- On 22 Feb 2012 at 16:11:58, Andrew Brouwer (andbrouwer.aaa.gmail.com) sent the message

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Dear All:

I have data from an in vivo study (oral administration) that is best

described by 1 comp model. I used WinNonlin model # 3 (1 comp) and model

# 5 ( 1 comp, K01 = K10). The later seems to fit the data better with

significantly lower CV% . I am just not sure when this assumption (K01 K10)

should be made. Should it be used in case of flip flop kinetics?

Any feedback about when model 5 is to be used will be greatly

appreciated.

Regards,

Andrew - On 23 Feb 2012 at 11:29:39, Ravi Bhatia (pharmarkb.-a-.gmail.com) sent the message

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The following message was posted to: PharmPK

Dear Andrew

I am not that much sure about using model 5, criterias can be

explained by experts in a better way.

But If K01=K10, it is supossed not to be flip-flop kinetics. Because

two basic assumption for flip-flop kinetics are:

(i)The terminal portion of the conc. time curve is not parallel for

Oral and IV data, and

(ii) Ka (Absorption rate constant) is much less than Ke (Elimination

rate constant)

You can refer VLASE L et. al. "PHARMACOKINETICS OF INTRAVENOUSLY

AND ORALLY ADMINISTERED MEMANTINE IN SWINE" FARMACIA, 2011, Vol. 59

You can also refer to earlier discussion at

http://www.pharmpk.com/PK03/PK2003324.html

Kind Regards - On 23 Feb 2012 at 11:11:48, "Shoaf, Susan" (Susan.Shoaf.-at-.otsuka-us.com) sent the message

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One more paper

Wijnand HP. Pharmacokinetic model equations for the one- and

two-compartment models with first-order processes in which the

absorption and exponential elimination or distribution rate constants

are equal. J Pharmcokinet Biopharmaceut. 1988;16:109-128.

Susan - On 23 Feb 2012 at 10:50:39, "Shoaf, Susan" (Susan.Shoaf.-a-.otsuka-us.com) sent the message

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The following articles might be of interest

Bialer M. A simple method for determing whether absorption and

elimination rate constants are equal in a one-compartment open model

with first-order processes. J Pharmacokinet Biopharmaceut 1980;8:111-3.

Chan KKH and Miller KW. Nonlinear regression approach for determining

whether absorption and elimination rate constants are equal in the

one-compartment open model with first-order processes. J Pharm Sci

1983;72:574-76.

Susan - On 23 Feb 2012 at 10:50:39, "Shoaf, Susan" (Susan.Shoaf.-at-.otsuka-us.com) sent the message

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The following message was posted to: PharmPK

The following articles might be of interest

Bialer M. A simple method for determing whether absorption and

elimination rate constants are equal in a one-compartment open model

with first-order processes. J Pharmacokinet Biopharmaceut 1980;8:111-3.

Chan KKH and Miller KW. Nonlinear regression approach for determining

whether absorption and elimination rate constants are equal in the

one-compartment open model with first-order processes. J Pharm Sci

1983;72:574-76.

Susan

[Are they ever equal except mathematically? I would be reluctant to set them equal during a modeling exercise. Your model needs to take into account the possibility that they are equal to avoid divide by zero but that can be done with an if statement or use of a differential equation model. - db] - On 24 Feb 2012 at 04:45:56, Simon Davis (Simon.Davis.-at-.certara.com) sent the message

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Hi Andrew, I think others on the list have given some good references -

I just wanted to add that model selection should also include using the

other diagnostic criteria that WinNonlin provides e.g. AIC, visual

inspection of fit, etc. and that it's better to assess all of the model

assessments as a whole (as well as it's intended use (Learn, Confirm,

Predict))

- rather than selecting on only one criteria. If you need to discuss

WinNonlin specific questions I welcome you to also join our discussion

forum at www.pharsight.com/extranet

Best regards,

Simon.

--

Simon.Davis.at.certara.com

Senior Scientific Consultant

Pharsight- A Certara(tm) Company

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