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Oiinkie ☆ The Netherlands, 2011-11-23 15:58 (4531 d 19:17 ago) Posting: # 7701 Views: 16,200 |
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Dear all, First, I would like to compliment HS and all contributors with the BEBAC site and forum. It has been and is an outstanding source of information with clear explanations and guidance on BE/BA. It has given me a thorough insight and great knowledge. Although this is my first post, I have been following the site and forum for the past two years, and now am feeling the need to ask for your wisdom on a specific issue regarding AUC(0-t). We, as a sponsor, have performed a BE study (N = 16, sampling up to and including t=72 h) in which we have established BE. Because we had major issues in the past with this CRO, specifically on the NCA PK and statistical analyses part, I also conducted all analyses. I used bear for R for these analyses, and double-checked them with SAS, SPSS (SPSS code available if anyone would be interested in how to analyze BE studies with SPSS) and PKSolver (add-in for M$ Excel). All results perfectly match. In comparison to the analysis by the CRO (the CRO uses WinNonlin and SAS), we have found a small difference in AUC(0-t), due to the following. One subject showed BLQ values for both T and R products at t=72h (although plasma concentrations for this subject are all on the low side, I cannot find any grounds to qualify him/her as an outlier). According to the protocol, BLQ values should be set to zero (indeed, from a mathematical perspective it would be much nicer to log-linearly extrapolate to t=72 h by using lambda z). The CRO omitted t=72 h values for this subject and calculated AUC(0-48) for this subject (in fact, according to the CRO, WinNonlin treated the data as such). I kept the 72 h time point in, set it to zero and calculated AUC(0-72) (i.e. an underestimation of “real” AUC(0-72)). In my opinion, as the samples at t=72 h were actually drawn and concentrations were not zero but BLQ (i.e. “measurable” but not “quantifiable”, if you get my point), I would opt to keep the values at t=72 h in for this subject (also to have a straight comparison from a statistical perspective). Obviously, the mean (arithmetic, geometric) AUC(0-t) is higher for both T and R in my calculation. Indeed, the definition of AUC(0-t) (i.e. “area under the plasma concentration curve from administration to last observed concentration at t”) can be explained in different ways, but I truly think that this time point has to be kept in the analysis. In the end, difference in PE and CV is very small, but still… CRO method (omit t=72 h for subject x): GMR PE = 92.40% CV = 13.99% My method (include t=72 h for subject x, set BLQ to zero): GMR PE = 92.48% CV = 14.01% What is your opinion on this issue? Would you omit or include t=72 for subject x in the AUC(0-t) calculation? Many thanks in advance! Best regards, Oiinkie — Regards, Oiinkie |
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d_labes ★★★ Berlin, Germany, 2011-11-23 16:42 (4531 d 18:33 ago) @ Oiinkie Posting: # 7702 Views: 14,540 |
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Dear Oiinkie! If you talk about AUC(0-tlast) your CRO has taken the right strategy. See this rather long thread with Helmut's fine explanation about various types of AUC calculations. If you talk about truncated area calculation AUC(0-72h) you will surely find this thread interesting. Although rather lengthy  .Hope this helps. — Regards, Detlew |
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Helmut ★★★   Vienna, Austria, 2011-11-23 17:09 (4531 d 18:05 ago) @ Oiinkie Posting: # 7703 Views: 15,867 |
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Dear Oiinkie! ❝ First, I would like to compliment HS and all contributors with the BEBAC site and forum. Thanks for the compliments! ❝ […] According to the protocol, BLQ values should be set to zero (indeed, from a mathematical perspective it would be much nicer to log-linearly extrapolate to t=72 h by using lambda z). I would also prefer the latter. ❝ The CRO omitted t=72 h values for this subject and calculated AUC(0-48) for this subject (in fact, according to the CRO, WinNonlin treated the data as such). Right, this is the default definition of AUCt in WinNonlin. ❝ I kept the 72 h time point in, set it to zero and calculated AUC(0-72) (i.e. an underestimation of “real” AUC(0-72)). In my opinion, as the samples at t=72 h were actually drawn and concentrations were not zero but BLQ (i.e. “measurable” but not “quantifiable”, if you get my point), I would opt to keep the values at t=72 h in for this subject (also to have a straight comparison from a statistical perspective). Well, as hard-core pharmacokineticists use to say: “There is only one concentration after a dose which we are certain that it does not exist: zero.” If you have stated to set all BLQ values to zero in the protocol, the CRO should have used Pharsight’s invention ‘AUCall’ which adds a triangle from the last time point where C > LLOQ to the next sampling time point. See this post and followings. ❝ Indeed, the definition of AUC(0-t) (i.e. “area under the plasma concentration curve from administration to last observed concentration at t”) can be explained in different ways, but I truly think that this time point has to be kept in the analysis. Right. In your case the subject’s 72 h values were BLQ after both formulations. The ratio of AUC48 will be unbiased (IR formulations = no flip-flop PK!). CVinter will increase – but not affecting the BE assessment. It’s getting nasty if C72 is BLQ after one treatment only. If we compare AUCt the ratio (e.g., AUC48/AUC72) will be biased away from 100%. Apples-and-oranges-statistics. At least members of the PK group were not concerned about this issue, claiming that the estimate will be conservative (i.e., shifting the point estimate away from 100% – increasing producer’s risk). I’m not sure whether this is true. IMHO the shift holds only for this particular subject’s ratio but may bias the study’s PE in any direction. ❝ What is your opinion on this issue? Would you omit or include t=72 for subject x in the AUC(0-t) calculation? I would use the estimated AUC72. Some people set the first concentration after the last measurable one to BQL/2 and consecutive ones to zero. There are such methods available in Phoenix/WinNonlin – the (in)famous ‘BQL-rules’. IMHO this is arbitrary and would make sense only if tz – tz-1 = t½.  Just a hint from PopPK: There are papers published comparing three methods – omitting BQLs, BQL/2, and C=0. If I recall it right: omitting gave the least bias and BQL/2 and C=0 performed almost equally worse. In the PopPK world most people nowadays set these values to BQL and use a one-sided (upper) truncated error (=censored) model for these values.Equivalence Trials – Proving that apples are pears by comparing the weight. Stephen Senn (2009) — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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d_labes ★★★ Berlin, Germany, 2011-11-24 10:21 (4531 d 00:54 ago) @ Helmut Posting: # 7708 Views: 14,057 |
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Dear Helmut! ❝ Well, as hard-core pharmacokineticists use to say: “There is only one concentration after a dose which we are certain that it does not exist: zero.” ... That would mean if I had taken Schützomycin once - knowing that already very very low concentrations cause it's extraordinary effects - I could fly for the rest of my life? What a nice imagination .— Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2011-11-24 18:28 (4530 d 16:47 ago) @ d_labes Posting: # 7716 Views: 13,999 |
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Dear Detlew! ❝ ❝ “There is only one concentration after a dose which we are certain that it does not exist: zero.” ... ❝ ❝ That would mean if I had taken Schützomycin once - knowing that already very very low concentrations cause it's extraordinary effects - I could fly for the rest of my life? What a nice imagination Here we must distinguish between PK and PD. Schützomycin is an undocumented ingredient of Flying Ointment but I can give you some details: M ~400 g·mol-1, usual dose 200 mg and almost complete (!) dermal absorption. With a half life of ~12 hours only one molecule (on the average, of course) is left in the circulation after 34 days… Unfortunately the wonderful effects diminish much much earlier. You can cross-dress as a witch and visit the Blocksberg next Walpurgis Night – I guess it’s possible to get a try-out there. BTW, what does “OT” in the subject line mean? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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d_labes ★★★ Berlin, Germany, 2011-11-25 09:46 (4530 d 01:28 ago) @ Helmut Posting: # 7717 Views: 14,132 |
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Dear Helmut! ❝ … With a half life of ~12 hours only one molecule (on the average, of course) is left in the circulation after 34 days… One molecule in a volume of ~5 litres (approx. 1/13 of body weight) of is of course very far from a concentration = zero  . But when it comes to this molecule feels lonesome and is also leaving the body (for Hard-core pharmacokineticists at time equal infinity) ... Of course you can argue along the lines of modern adepts of Samuel Hahnemann's homeopathy: "Then the water in the body has at least a memory for Schützomycin!" but the concentration is nevertheless zero. End of 'Krümelkackerei' .❝ BTW, what does “OT” in the subject line mean? - German wikipedia: 4th entry ("Begriff des Netzjargons"). - English version: 2nd entry under the topic 'Other' — Regards, Detlew |
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Oiinkie ☆ The Netherlands, 2011-12-05 15:25 (4519 d 19:49 ago) @ Helmut Posting: # 7759 Views: 13,957 |
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Dear HS and d_labes, Thank you very much for your reply and explanations! Best regards, Oiinkie — Regards, Oiinkie |
Ing. Helmut Schütz