Sasi ☆ 20080610 10:44 (edited by Jaime_R on 20080610 11:48) Posting: # 1933 Views: 22,293 

Dear all in BA/BE study i need to calculate AUC072 instead of AUClast and AUCinf how can i calculate this value by using winnonlin. How many minimum concentrations requried for calculation of t1/2 and Kel. Thanks and regards sasi  Edit: Category changed. [Jaime] 
Jaime_R ★★ Barcelona, 20080610 12:18 @ Sasi Posting: # 1934 Views: 19,995 

Hi Sasi! » ... i need to calculate AUC072 instead of AUClast and AUCinf how can i calculate this value by using winnonlin. I'm not sure whether I understand your question.
» How many minimum concentrations requried for calculation of t1/2 and Kel. For the estimation of k_{el} 3, for the calculation of t_{½} zero. SCNR — Regards, Jaime 
Ohlbe ★★★ France, 20080610 17:28 @ Jaime_R Posting: # 1935 Views: 20,031 

Dear all, » » How many minimum concentrations requried for calculation of t1/2 and Kel. » » For the estimation of k_{el} 3, for the calculation of t_{1/2} zero. SCNR What is the point in calculating k_{el} and t_{½}, if you are using truncated AUC ? If you are truncating your AUC at 72 h, it probably means that you have a drug with a long terminal halflife. The points you have till 72 hours may not be sufficient and adequate to provide a reliable estimate of k_{el}. Regards Ohlbe 
Jaime_R ★★ Barcelona, 20080610 18:45 @ Ohlbe Posting: # 1936 Views: 19,835 

Dear Ohlbe! » What is the point in calculating k_{el} and t_{1/2}, if you are using truncated AUC ? Of course you are right; estimating k_{el} in a truncated setting doesn't make any sense! I answered too quickly (minimum 3 points...) and forgot the post's subject line. Sorry. — Regards, Jaime 
d_labes ★★★ Berlin, Germany, 20090618 09:26 @ Jaime_R Posting: # 3872 Views: 18,856 

Dear Ohlbe, dear Jaime, dear all, let me share some experience with regulators in the EMEA. In a recent submission of a BE study with a long halflife product (t_{1/2} from literature about 5070 h) we submitted an evaluation with AUC(072h), C_{max} and t_{max} as metrics, the typical truncated area setting. Regulators response: The Germans asked for AUC(0inf)! The French asked for lamda_{Z} (k_{el}) and t_{1/2}! Hopefully they will not ask for residual area <20% . — Regards, Detlew 
Ohlbe ★★★ France, 20090618 10:37 @ d_labes Posting: # 3874 Views: 18,751 

Dear D. Labes, » Regulators response: » The Germans asked for AUC(0inf)! » The French asked for lamda_{Z} (k_{el}) and t_{1/2}! » » Hopefully they will not ask for residual area <20% . I hesitate between and Regards Ohlbe — Regards Ohlbe 
Helmut ★★★ Vienna, Austria, 20090618 14:49 @ d_labes Posting: # 3875 Views: 18,813 

Dear D. Labes, Oh, my sweet Lady Justice... To be honest, which kind of 'truncation' are you dreaming of? — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
d_labes ★★★ Berlin, Germany, 20090618 15:26 @ Helmut Posting: # 3877 Views: 18,772 

Dear Helmut, after long thinking I would go for (a) + (b) + (c) and additionally for keelhauling under the command of ElMaestro. I have a suggestion: What about holding your fine lectures especially for regulators? Eventually the great EMEA pays a good price. Now leaving for Salzburg to visit your fine country and the birthplace of "Wolferl" Mozart. I hope to forget for a while ... — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20090618 15:44 @ d_labes Posting: # 3878 Views: 18,870 

Dear D. Labes, » keelhauling under the command of ElMaestro. Must be fun! » I have a suggestion: What about holding your fine lectures especially for regulators? Oh, some of them are regularily listening to my lectures with great disgust. » Eventually the great EMEA pays a good price. Great idea. Normally I’m not paid to give presentations. The Austrian Agency asked me back in 2000, but were shocked by the quotation. The only regulatory authority asking me recently was the Saudi FDA . Since I don’t wear suits (don't even own one) I asked about dresscode being told that jeans/jacket would be OK. » Now leaving for Salzburg to visit your fine country and the birthplace of "Wolferl" Mozart. If possible avoid the Getreidegasse! — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
ElMaestro ★★★ Belgium?, 20090619 22:16 @ Helmut Posting: # 3883 Views: 18,781 

Oh, did the Saudi FDA also try to get you to do the oneweek tuition? How was it? I would have loved to go, but couldn't for a number of reasons. But then again, Belgian sailors ain't of much use in the desert. EM. 
Helmut ★★★ Vienna, Austria, 20090619 22:35 @ ElMaestro Posting: # 3884 Views: 18,874 

Ahoy! » did the Saudi FDA also try to get you to do the oneweek tuition? They asked for a workshop – whateverthatmeans. » How was it? Wrong tempus. They asked me already two years ago, and nothing happened – last month again. I’m not the type of guy doing client acquisition. If they really want me to go, they will come up again; if not – not. » But then again, Belgian sailors ain't of much use in the desert. Yeah, but SA has a quite lengthy shoreline with some nice harbors. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
ElMaestro ★★★ Belgium?, 20090618 14:50 @ d_labes Posting: # 3876 Views: 18,883 

"Forgive them, for they know not what they do." EM. 
d_labes ★★★ Berlin, Germany, 20080905 15:00 @ Ohlbe Posting: # 2323 Views: 19,739 

Dear Ohlbe, dear Jaime, dear all, I would like to discuss this a bit further. How do you act in a truncated setting if the last sample is missing? Or if some subject has conc. <LOQ due to faster kinetics? Omit this subject from the analysis? Or try to extrapolate to t=72h? If extrapolation is an option for you: how? Using an estimate of lamda_{Z} or by the last preceding 2 points? — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20090126 16:24 @ d_labes Posting: # 3123 Views: 19,576 

Dear D. Labes, sorry for the late response – I was driven by discussions about the drafted European BEGuideline. » I would like to discuss this a bit further. » How do you act in a truncated setting if the last sample is missing? Or if some subject has conc. <LOQ due to faster kinetics? » » Omit this subject from the analysis? I have heard of CROs omitting subjects if AUC_{72} was stated as the primary parameter and the sample at 72 h (or earlier) was ≤LOQ. In the strict sense I would consider this correct. But: with the current trend of moving from seening BE as a surrogate of clinical safety/efficacy to a measure of pharmaceutical performance in vivo I would go with Kamal Midha’s Mantra and accept AUCs where the absorption is completed (C_{last} ≥2–4 times t_{max}). See Example 2 in this thread. If we truncate AUCs of subjects with C_{last}<72 (for any treatment) at the last time point where C>LOQ (for all treatments), it should be possible to get an unbiased estimate of the T/Rratio.* Unfortunately this method is not available in commercial software (at least not in the current versions of WinNonlin, Kinetica, EquivTest/PK). I wouldn’t start trying to get an estimate of C_{72}. Edit (years later)
— Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
d_labes ★★★ Berlin, Germany, 20090126 16:57 @ Helmut Posting: # 3125 Views: 19,189 

Dear Helmut, » sorry for the late response – I was driven by discussions about the drafted European BEGuideline. "Late is not too late". I am with you if the values in the last part of the concentration time course are <LOQ. But I think it's different with missing values (vial broken or so) especially in case of long half life drugs. Because time points are spread occasionally with 24h in the last part, there may be a considerable portion of AUC missing. » I wouldn’t start trying to get an estimate of C_{72}. Is this sentence then furthermore your opinion? — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20090126 17:20 @ d_labes Posting: # 3126 Views: 19,222 

Dear D. Labes, » I am with you if the values in the last part of the concentration time course are <LOQ. But I think it's different with missing values (vial broken or so) especially in case of long half life drugs. If a value is missing – or even came up as <LOQ in repeated analyses – and is included within values which are clearly (!) above LOQ I routinely substitute such a value by a (log)interpolated estimate. I have such a procedure since decades (oh, I’m getting old) in my protocols, and never got any problems. » Because time points are spread occasionally with 24h in the last part, there may be a considerable portion of AUC missing. This wouldn’t bother me as long as C_{last} ≥2–4 times t_{max}. » » I wouldn’t start trying to get an estimate of C_{72}. » » Is this sentence then furthermore your opinion? Yes. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
d_labes ★★★ Berlin, Germany, 20090127 11:48 @ Helmut Posting: # 3137 Views: 19,306 

Dear Helmut, » ... I have such a procedure since decades (oh, I’m getting old) in my protocols ... Don't lose heart! Getting old is not for sissies (Bette Davis) ! I have the vague suspicion that I have not explained my point precise enough. So let me give an example (real data):
time Conc. Half live for this curve with no missings is 53.6 h (using points 1272 h). AUC(072)=584.93 (linear trapezoidal rule for sake of simplicity). If now the conc. value at 72h is missing unfortunately (vial broken or so), what to do? AUC(048h) is 437.21, considerably lower than AUC(072), only 75%.
Other users also a position? — Regards, Detlew 
Ohlbe ★★★ France, 20090128 00:00 @ d_labes Posting: # 3148 Views: 19,233 

Dear D. Labes, » 1. Option: Exclude subject » 2. Option: Use AUC(048) » 3. Option: Extrapolate to 72h (C(calc.)=5.69 using loglin regression with * points) and calculate then AUC (result =595.85). Whichever option you select, you can be sure there will be an Agency to say it was the wrong one... (At least the French Agency, I guess ) » 1. Option: Exclude subject They will hate that... They will be afraid that you may pretend to have broken a tube in order to remove a subject with "annoying" results... » 2. Option: Use AUC(048) I suppose you would do that for both treatments. In a way you would introduce a bias by using an underestimated AUC... And you might be suspected again of playing with the data. » 3. Option: Extrapolate to 72h (C(calc.)=5.69 using loglin regression with * points) and calculate then AUC (result=595.85). Introducing another bias. The question will be, how reliable is your estimate ? It will depend on the PK of the drug (mono or multicompartmental), sampling times, etc. (Basically, if you remove the last sample, will the calculated halflife still be the terminal halflife ?). Probably closer to the truth than Option 2, but they may refer to the current EU guideline: "The exclusive use of compartmental based estimates are not recommended", and forget about "exclusive". I'm not even sure my opinion would be worth twopence here, but... write in your protocol what you would do in such a situation, do it this way, and keep you fingers crossed, hoping for your file to be reviewed by an assessor with not more than 30 or 60 minutes on his hands (ElMaestro would say you have good chances). Regards Ohlbe 
martin ★★ Austria, 20090128 08:26 @ Ohlbe Posting: # 3150 Views: 19,079 

dear ohlbe ! what do you think about a sensitivity analysis? best regards martin Ps.: in my opinion the best way to handle this issue is to perform a blinded review and specify the method how you will handle this issue (may be motivated by sensitivity analyses in combination with monte carlo methods) 
d_labes ★★★ Berlin, Germany, 20090128 09:54 @ Ohlbe Posting: # 3151 Views: 19,041 

Dear Ohlbe, » Whichever option you select, you can be sure there will be an Agency to say it was the wrong one... (At least the French Agency, I guess ) Is it that evil with your experience with regulators? » [...] I'm not even sure my opinion would be worth twopence here [...] I would pay 4 cents (Euro cents of course) . Thanks for your valuable opinion. — Regards, Detlew 
Ohlbe ★★★ France, 20090128 10:16 @ d_labes Posting: # 3152 Views: 19,058 

Dear D. Labes, » » Whichever option you select, you can be sure there will be an Agency to say it was the wrong one... (At least the French Agency, I guess ) » » Is it that evil with your experience with regulators? Andrew Leary wrote that 'The English are a strange bunch who take pleasure in disagreeing with everyone else'. In France this is not a pleasure, but a very serious and fulltime job . Best regards Ohlbe 
ElMaestro ★★★ Belgium?, 20090128 14:32 @ d_labes Posting: # 3155 Views: 19,345 

» 1. Option: Exclude subject » 2. Option: Use AUC(048) » 3. Option: Extrapolate to 72h (C(calc.)=5.69 using loglin regression with * points) and calculate then AUC (result=595.85). Hi, I'd go for option 3 (after all we are used to extrapolations when it comes to AUCinf and nobody has a problem with that. If you can extrapolate something to inf then why not to 72 hrs. as well?!). Excluding a subject is a possibility if something went wrong (vial broken, a UFO landed and the chromatograph melted, etc). The CHMP has been working a lot on aspects of missing values etc, and they have come up with all sorts of strange concepts that have very little relevance for this situation. Finally, depending on the combo of RMS and CMSs it might not make a difference at all what you choose. Of course, if you advertise in a very clear manner that something is fishy in the dataset then you might be able to force the assessor to look into it, but why not just leave it as it is and mention it on page 3848 and hope for the best. Martin: 'Sensitivity analyses' (them being a lot of things) are probly a good idea. But it has absolutely no focus for PK assessors at the moment. But in a centralised procedure with survival curves the CHMP will sing with loud and clear voice "oh yeah, gimme gimme gimme sensitivity analyses" EM. 
d_labes ★★★ Berlin, Germany, 20090128 14:51 @ ElMaestro Posting: # 3156 Views: 19,171 

Dear ElMaestro, » [...] to force the assessor to look into it, but why not just leave it as it is and mention it on page 3848 and hope for the best. Very good idea! I will add always a page 3848 to my 221 (or so) pages PK report in the future! All jokes aside. Thanks for your points. I agree with you. — Regards, Detlew 
Astea ★★ Russia, 20170311 20:14 @ d_labes Posting: # 17149 Views: 10,459 

Dear all! Sorry for reviving the battered topic but for validation purposes I need to understand the methods of calculating partial areas in some nasty cases. I have a premonition that it would be hard to understand my question so I’ll try to use more illustrations… Suppose we have to calculate AUC_{072}. The biggest problem is to decide: to extrapolate or nor to extrapolate. Let us follow the first scene. Suppose that the protocol states to use a simple linear trapezoid method to calculate AUC. How to calculate AUC_{072} in the following situations?
To compare different methods I used the following concentrationtime table:
time Conc. 1. Let us start with the first case: as it is intuitevily simple we just use a linear approximation to zero point. It is hard to invent an alternative approach because it is difficult to approximate by a known function the absorbtion part of the curve. Only if there was a nonzero concentration in the first sample (not enough washout or some unsufficient endogenous calculation) the results would differ. AUC_{last}=AUC_{all}=AUC_{072}=8391 2. To calculate AUC_{072} (AUC truncated) for the cases with t_{last}>72 h we can just truncate (cut down) at the time t=72 h (see the upper picture). For t_{last}=73: AUC_{last}=AUC_{all}=8479.5; AUC_{072}=8402.0 But when we deal with t_{last}<72 h there appear different opportunities to get the value at t=72 h: a). rude linear approximation (over the two last values or over the elimination period) For t_{last}=71: C_{72}=76 b). loglinear interpolation (over the elimination period) For t_{last}=71: C_{72}=76.84 ( AUC_{last}=AUC_{all}=8302.5); After assessing the concentration at 72 h we have to calculate the area under the last curve. It can be done via:  linear trapezoid method (С_{1}+C_{2})/2*(t_{2}t_{1}) AUC_{072}=8379.0  log trapezoid method (С_{1}C_{2})/(ln С_{1}lnC_{2})*(t_{2}t_{1}) AUC_{072}=8376.9 I can’t imagine what else there could be done. What method does WinNonLin use if it gets a value 8379.421 (very close to linear interpolation but not equal to it) 3. If there were no samples at t=72 h, the last point can be approximated by linear or loglinear interpolation and area can be calculated via linear or log trapezoid as in the previous case. Comparing the results of the calculation I conclude that in this case WinNonLin use:  Loglinear interpolation and log trapezoid method to calculate AUC_{072}. AUC_{last}=AUC_{all}=6267; AUC_{072}=7983.3 The question arises: is it not strange to calculate the last part by log trapezoid method while the whole curve is calculated via untransformed trapezoid? Of course log interpolation is more preferable for the elimination part of the curve but we initially stated to use untransformed method. Why does the situations 2) and 3) have different solution methods? — "Being in minority, even a minority of one, did not make you mad" 
mittyri ★★ Russia, 20170316 19:46 @ Astea Posting: # 17159 Views: 10,360 

Dear Astea, » 1. There were time deviations in the first point (that is instead of t_{0}=0, we have, for example, t_{0}=1 hour) I didn't get this. Does that mean the deviation in dosing time or what? » 2. There were time deviations in the last sample point (that is instead of t_{last}=72 h we have t_{last}=71 h or t_{last}=73 h). Additionally what if we have concentrations below LLOQ in the several last points (agree it is strange for drugs with long halflife but who knows..)? » 3. There were abscent samples (NA) at the last time point 72 h I think all options are described in WNL Guide:
» The question arises: is it not strange to calculate the last part by log trapezoid method while the whole curve is calculated via untransformed trapezoid? Of course log interpolation is more preferable for the elimination part of the curve but we initially stated to use untransformed method. Then we need to use another lambda for 'linear regression', right? How to calculate it? Should we use some rules for it? How many points do we need? So many questions as you see... Think about WNL Partial Areas rules as about huge combination of compromises. You're free to create your own rules in WNL or in R or other data management/plotting tool. » Why does the situations 2) and 3) have different solution methods? Different ClastPreds, different Lambdas, different solutions — Kind regards, Mittyri 