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Partial AUC not being calculated, despite no deviations to sample time?

partial AUC

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#1 simon.hutchings

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Posted 18 November 2019 - 05:50 PM

Hi Phoenix WNL community,

 

I am running analysis where AUC0-10h is a required parameter, with samples taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, and 10 hours.

 

I understand that lambda_z is used to estimate the concentration at the 10 h time point for any instances where there is a bleed time deviation (and therefore there is not an observed concentration exactly at 10 h), and therefore AUC0-10 will not be estimated for any instances where:

 

a) there is a bleed time deviation at the 10 h time point, and

B) the elimination rate constant was not estimable

 

However, for one profile there was no deviation at the 10 h time point but AUC0-10 has not been estimated.  I cannot work out why this is.  I note that there are only values above the LLOQ at the 0.5, 2, 4.5 h, with BLQs from 5 h onwards... could this be why?

 

Thanks for any help with this!

 

 



#2 bwendt@certara.com

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Posted 18 November 2019 - 05:55 PM

Hi Simon,

 

if you have only 3 data points in your profile and one of those is Tmax/Cmax you are one point too short for one of the requirements to estimate Lambda_z: 3 measured concentrations after Tmax. 

Can you please check the Warnings and Error output under Results, this should give you some indication. If you want another proof, you may want to share your project file - if not here - you can send it to support@certara.com.

 

Bernd 



#3 simon.hutchings

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Posted 19 November 2019 - 09:13 AM

Hi Simon,

 

if you have only 3 data points in your profile and one of those is Tmax/Cmax you are one point too short for one of the requirements to estimate Lambda_z: 3 measured concentrations after Tmax. 

Can you please check the Warnings and Error output under Results, this should give you some indication. If you want another proof, you may want to share your project file - if not here - you can send it to support@certara.com.

 

Bernd 

 

Hi Bernd,

 

Thanks very much for the swift response.  I understand that lambda_z could not be estimated from this profile, but was wondering if the trapezoidal rule could not be used from the last value above LLOQ (4.5h) out to 10h?

 

Simon



#4 bwendt@certara.com

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Posted 19 November 2019 - 02:29 PM

Hi Simon,

 

since NCA only has values up to 4.5h and no value for 10h it would need to calculate a concentration at 10h. It cannot do this without lambda_z. 

From Phoenix online help:

 

If a start or end time falls after the last numeric observation and Lambda Z is not estimable, the partial area will not be calculated.

 

When you switch on Intermediate output in the bottom panel of the NCA object it will show you a warning in the Core Output:

 

Intermediate Output: Partial Areas
----------------------------------
Computing partial area from 0.000000 to 10.000000:
 
*** Warning 14530: Lambda_z could not be estimated.
No parameters could be extrapolated to infinity.
 
 
Hope, this helps.
 
Bernd


#5 Linda Hughes

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Posted 19 November 2019 - 02:30 PM

Hi Simon,

Bernd's comment refers to the best-fit method for Lambda_z.  If you think it is appropriate, there are a couple ways in which you can intervene.  One is to supply a time range for computing Lambda_z, either using the last two points or all three points, whichever you think is more appropriate for your data.  Another is to supply a value at time 10, such as zero or LLOQ/2, whichever you think is more appropriate.

I think this latter method is what you are suggesting in your comment "wondering if the trapezoidal rule could not be used from the last value above LLOQ (4.5h) out to 10h'.  A value would have to be supplied at 10h to do this.
Regards,

Linda Hughes



#6 simon.hutchings

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Posted 19 November 2019 - 03:38 PM

 

Hi Simon,

 

since NCA only has values up to 4.5h and no value for 10h it would need to calculate a concentration at 10h. It cannot do this without lambda_z. 

From Phoenix online help:

 

If a start or end time falls after the last numeric observation and Lambda Z is not estimable, the partial area will not be calculated.

 

When you switch on Intermediate output in the bottom panel of the NCA object it will show you a warning in the Core Output:

 

Intermediate Output: Partial Areas
----------------------------------
Computing partial area from 0.000000 to 10.000000:
 
*** Warning 14530: Lambda_z could not be estimated.
No parameters could be extrapolated to infinity.
 
 
Hope, this helps.
 
Bernd

 

 

Hi Bernd, thank you for the follow-up. I think from your response and Linda's below I understand better and have a way forward.



#7 simon.hutchings

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Posted 19 November 2019 - 03:40 PM

Hi Simon,

Bernd's comment refers to the best-fit method for Lambda_z.  If you think it is appropriate, there are a couple ways in which you can intervene.  One is to supply a time range for computing Lambda_z, either using the last two points or all three points, whichever you think is more appropriate for your data.  Another is to supply a value at time 10, such as zero or LLOQ/2, whichever you think is more appropriate.

I think this latter method is what you are suggesting in your comment "wondering if the trapezoidal rule could not be used from the last value above LLOQ (4.5h) out to 10h'.  A value would have to be supplied at 10h to do this.
Regards,

Linda Hughes

 

Thank you Linda this is most helpful







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