4 replies to this topic

[OLUMUYIWA ADEDEJI]

I copied the statements from page 49-50 of Phoenix Winnolin 6.3 Examples Guide:

 

"Terminal elimination phase

Phoenix attempts to estimate the rate constant, , associated with the terminal

elimination phase. Although Phoenix is capable of selecting the times to be used

in the estimation of , this example provides Phoenix with the time range.

Specify the times to be included:

There are two ways to specify the times to be included.

1. Select Slopes Selector in the Setup list.

2. Select Time Range in the Lambda Z Calculation Method menu.

3. In the Start field type 8.

4. In the End field type 24.

 

Therapeutic response

The next step is to define a target concentration range to enable calculation of

the time and area located above, below, and within that range.

Note: See Noncompartmental analysis with exclusions, computing partial areas on

page 46 for an NCA example that includes computation of partial areas under

the curve.

Specify the therapeutic response options:

1. Select Therapeutic Response in the Setup list.

2. Select the Use internal Worksheet check box.

The Therapeutic Response sorts dialog is displayed. The Therapeutic Response

sorts dialog prompts the user to select the sort variables to use to create the

internal dosing worksheet.

3. Click OK to accept the default sort variable."

4. Select Therapeutic Response in the Setup list.

5. In the Lower cell for each subject type 2.

6. In the Upper cell for each subject type 4."

 

My Query: In the terminal elimination phase, I understood why 8(h) and 24(h) were typed being sampling times. But in Therapeutic response, Why do we need to type 2(h) and 4(h)? Could we have typed 1(h) and 2(h) or 3(h) and 6(h).

As a scientist, we must know the basics to understand a phenomenom better. There are some other areas (pg 93) in the guide where the instruction would just say type or enter value V_F = 0.25

• K01 = 1.81

• K10 = 0.23

[Simon Davis]

Hi Olumuyiwa,
It's a good question to ask and I'm glad to see people checking the scientific validity of exercises. In this case the confusion is you have assumed that the values of the therapeutic response are units of time but if you read the description again you will see the text;

The next step is to define a target concentration range to enable calculation of
the time and area located above, below, and within that range.

so the values you are entering are a lower concentration range of 2 and an Upper range of 4, i.e. the therapeutic window you are seeking to quantify is between these two levels, does that make sense?

Simon

PS regarding the question on (page 83 actually), this section is on compartmental modelling so these are the initial estimates for the algorithm to commence is search for the optimal solution. I just put a graphic together to give an indication of how you might get an estimate of volume (note the examples guide is using a value of 0.25 L

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[OLUMUYIWA ADEDEJI]

Dear Simon,

Thank you for your exposition. T get the picture clearer, I have follow-up questions

Therapeutic Response.

My question is, how do we determine the lower and upper concentration ranges (2 & 4)

From the file used, Bguide1.dat, the lowest concentration is 1.287. Are these concentrations hypothetical for demonstration?

 

Also pardon my naivety, I am just getting understanding of pg 83 with your explanation on V_F.

I also understood by corollary that K10 = 0.23 which is elimination rate constant was gotten from Lamda_Z obtained from PK parameters after execution (Hope I am right?). How do we get the absorption rate constant(Ka) K01 = 1.81?

Could you use figure to illustrate too?

Many thanks.

[Linda Hughes]

For your first question, the values 2 and 4 are hypothetical for demonstation. In practice, these values come from information about a particular drug rather than from the data. Lower might be the minimum concentration at which the drug becomes therapeutic, and Upper might be the concentration over which there are significant safety concerns. You could use other values.

 

Regards,

Linda Hughes

[Simon Davis]

Dear Olumuyiwa,

  There is a little more work to getting absorption rate constant (Ka), but an initial estimate canbe obtained by a method known as “curve stripping" (also I have heard it called, “feathering” or “method of residuals”).

 

  If you are a beginner it might be useful to have a text book to take you through this, e.g. this technique is detailed on p377 of the following text book.

 

http://www.certara.com/pk-pd-textbook/

 

  Or if you search for curve stripping on the web you can find some nice introductory texts e.g. p 11 of the following PDF.

 

http://www.pharmpress.com/files/docs/php-bph-c06.pdf

 

  Simon