Louis52 ☆ 20180207 21:04 Posting: # 18375 Views: 11,316 

Hello, Can anyone direct me towards a thread where it is discussed/presented how to deal with alpha adjustment and power in case of multiplicity (AUC and Cmax considered at the same time)? Both CO and Parallel designs. Thanks! 
ElMaestro ★★★ Belgium?, 20180207 22:37 @ Louis52 Posting: # 18376 Views: 10,590 

Hi Louis, » Can anyone direct me towards a thread where it is discussed/presented how to deal with alpha adjustment and power in case of multiplicity (AUC and Cmax considered at the same time)? Both CO and Parallel designs. There is no alpha adjustment. You need to show BE for both, usually. Sometimes even AUC in several flavours. AUC and Cmax are positively correlated. That's something you may wish to factor in for sample size. However, in practice this requires a model for the correlation itself (for which nothing generally can be said) and besides it actually works quite well if you just dimension it according to the worstcase metric which tends to be Cmax. — I could be wrong, but... Best regards, ElMaestro 
d_labes ★★★ Berlin, Germany, 20180208 14:12 @ Louis52 Posting: # 18381 Views: 10,633 

Dear Louis, » Can anyone direct me towards a thread where it is discussed/presented how to deal with alpha adjustment and power in case of multiplicity (AUC and Cmax considered at the same time)? Both CO and Parallel designs. have a loook at this post or this one. As our ElMaestro already said: According to the intersectionunion principle there is no need for adjusting alpha if you combine two TOST with AND. As long as the two combined test on their own have size alpha. Power is another pair of shoes. If the correlation is zero, the overall power is the product of the powers of the individual tests, i.e. may be considerable lower then the targeted power. If the correlation is one, the overall power is the minimum of the powers of the individual tests. This is the foundation why we make a sample size calculation for both metrics and choose the resulting higher sample size. But no one knows, at least not me, to what number the correlation should be set in practice. The authors team of the R package PowerTOST is currently discussing that theme. May be we came out with some aid in the near future.Be aware: It is not the correlation of the two PK metrics itself. To cite from the man page of function power.2TOST() :"rho: Correlation between the two PK metrics (e.g. AUC and Cmax) under consideration. This is defined as correlation between the estimator of the treatment difference of PK metric one and the estimator of the treatment difference of PK metric two." Be further aware: The functions for power and sample size for the combination of 2 TOST are currently under revision since the implemented versions in V1.46 came out as statistical flawed. You need the development version of PowerTOST to get reliable values for the power of 2 TOST. See this thread how to get it. Reference to look into: Phillips KF. Power for Testing Multiple Instances of the Two OneSided Tests Procedure Int J Biostat. 2009;5(1):Article 15. doi:10.2202/15574679.1169 — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20180208 21:40 @ d_labes Posting: # 18382 Views: 10,530 

Hi Louis, » But no one knows, at least not me, to what number the correlation should be set in practice. » The authors team of the R package PowerTOST is currently discussing that theme. May be we came out with some aid in the near future.Current state of affairs about the mysterious ρ: Runtime 0.78 seconds. 6176 subjects in 124 data sets of 98 2×2×2 studies (74 analytes). PS: No, I’m not underpowering my studies for C_{max}. Some were so old that they were powered for an acceptance range of 75–133% or even 70–143%. _{} Was too lazy to browse through the protocols… — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
ElMaestro ★★★ Belgium?, 20180209 09:58 @ Helmut Posting: # 18385 Views: 10,452 

Hi Helmut, thank you for the info. Out of curiosity, could you show a histogram of lnPEAUClnPECmax ? Muchas gracias — I could be wrong, but... Best regards, ElMaestro 
Helmut ★★★ Vienna, Austria, 20180209 19:20 @ ElMaestro Posting: # 18389 Views: 10,425 

Hi ElMaestro, » Out of curiosity, could you show a histogram of lnPEAUClnPECmax ? Other way ’round: — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
ElMaestro ★★★ Belgium?, 20180209 11:32 @ Helmut Posting: # 18387 Views: 10,443 

Hi Helmut, I have a bonus question, although not about the correlation itself. If I look at the location of your PE's on the horisontal axis (the AUC axis) then it looks to me like there are more points on the higher side of 1 than on the lower side. Perhaps it is only a graphical artifact? Or something with the selection of studies plotted? If not, then I wonder why that wold be so? I imagine you don't really have the answer but I am curious about any speculation from your side or from others. My head is already abuzz with stabilities and overages and much other weird stuff from the odd sock drawer of speculation. If this is not an artifact then I am almost thinking this would be worth a publication (if it had no already been shown here). Same might apply for the vertical axis, not sure. Perhaps I am only hallewcinating? — I could be wrong, but... Best regards, ElMaestro 
Helmut ★★★ Vienna, Austria, 20180209 19:43 @ ElMaestro Posting: # 18390 Views: 10,424 

Hi ElMaestro, updated version: Runtime 0.92 seconds. 7470 subjects in 142 data sets of 114 2×2×2 studies (86 analytes). » If I look at the location of your PE's on the horisontal axis (the AUC axis) then it looks to me like there are more points on the higher side of 1 than on the lower side. cat(sprintf("%.1f%%", 100*sum(PE.AUC > 1)/length(PE.AUC)), ">1\n"); summary(PE.AUC, digits=4) » Same might apply for the vertical axis, not sure. Perhaps I am only hallewcinating? » Perhaps it is only a graphical artifact? cat(sprintf("%.1f%%", 100*sum(PE.Cmax > 1)/length(PE.Cmax)), ">1\n"); summary(PE.Cmax, digits=4) » Or something with the selection of studies plotted? Duno. In the meantime I removed two studies (one was a tablet vs. a suspension and the other one from Hauschke/Steinijans – two MRs but the target was “flatter is better”) and added a couple more. It was easy to import the data but now I have to check in the protocols what the target was. Not always stated in the title and boring reading matter. Will take a while. » If not, then I wonder why that wold be so? I imagine you don't really have the answer but I am curious about any speculation from your side or from others. My head is already abuzz with stabilities and overages and much other weird stuff from the odd sock drawer of speculation. You are not alone. I have more questions than answers myself. Most circle around which ones to include:
when I don’t know what I’m doing. Wernher von Braun — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Astea ★ Russia, 20180209 20:47 @ Helmut Posting: # 18392 Views: 10,436 

Dear all! I tried to repeat the Helmut's conclusions. I used 70 datasets from 63 2x2x2 studies. My rho is 0.797 for untransformed data and 0.799 for logtransformed. Meanwhile it tends to have the inverse situation, that is there are more values lower than 100 comparing to those uper than 100 (66% for Cmax and 63% for AUC). Suppose it is just an artefact of low sample size.. P.S. One dummy's question about PowerTOST from GitHub: while trying to do devtools::install_github("Detlew/PowerTOST") I got:
package ‘mvtnorm’ successfully unpacked and MD5 sums checked Should I delete it manually or ...what to do? — "We are such stuff as dreams are made on, and our little life, is rounded with a sleep" 
d_labes ★★★ Berlin, Germany, 20180211 13:23 @ Astea Posting: # 18394 Views: 10,272 

Dear Nastia » P.S. One dummy's question about PowerTOST from GitHub: while trying to do devtools::install_github("Detlew/PowerTOST") I got: »
» package ‘mvtnorm’ successfully unpacked and MD5 sums checked That error occasionally occures if you try to install a package which is in use, especially some dll (compiled code) is in use. » Should I delete it manually or ...what to do? Yes my dear, delete any leftover of ‘mvtnorm’ and install again, of course in a fresh R console. — Regards, Detlew 
d_labes ★★★ Berlin, Germany, 20180211 15:57 @ Helmut Posting: # 18395 Views: 10,225 

Dear Helmut! Dear all! » Current state of affairs about the mysterious ρ That's not the whole truth about the state of affairs . The question is: Correlation of treatment differences between studies or within studies. For the latter I recall you two references: Phillips KF. Power for Testing Multiple Instances of the Two OneSided Tests Procedure Int J Biostat. 2009;5(1):Article 15. doi:10.2202/15574679.1169 Hua SY, Xu S, D’Agostino RB Sr. Multiplicity adjustments in testing for bioequivalence Stat Med. 2015;34(2):215–31. doi:10.1002/sim.6247 Quote from Kem Phillips: "The correlation will usually be difficult to estimate, unless a similar experiment has been conducted...". That smells for me like within a study. Definition in Hua et al., Section 2, clearly is within a study. Although Ben doubt the correctness of the formulas for ρ given in that paper. Note further that the observed alphainflation in that paper is crap. The IUT principle protects us from the need to adjust alpha. — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20180211 17:31 @ d_labes Posting: # 18396 Views: 10,173 

Dear Detlew » That's not the whole truth about the state of affairs . » The question is: Correlation of treatment differences between studies or within studies. » » For the latter I recall you two references: » Phillips KF. » Power for Testing Multiple Instances of the Two OneSided Tests Procedure » Int J Biostat. 2009;5(1):Article 15. doi:10.2202/15574679.1169 » » Quote from Kem Phillips: » "The correlation will usually be difficult to estimate, unless a similar experiment has been conducted...". » That smells for me like within a study. Yep, then I expect a high correlation (based on my limited knowledge of PK). For my data sets I get with pearson < cor.test(log(study$AUC), log(study$Cmax)) IIRC, Chow & Liu state somewhere that the mean of withinsubject ratios is a biased estimate… Another question: What is a “similar experiment”? Given the dispersion in the summary above I would rather say that trying to get an estimate across different drugs (or even for the same drug but IR/IR and MR/MR) is futile. Will try again with the analyte as a factor. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
d_labes ★★★ Berlin, Germany, 20180211 19:21 @ Helmut Posting: # 18399 Views: 10,232 

Dear Helmut, » Yep, then I expect a high correlation (based on my limited knowledge of PK). For my data sets I get with » pearson < cor.test(log(study$AUC), log(study$Cmax)) » rho[set, "estimate"] < pearson$estimate Thanks for that numbers. » Another question: What is a “similar experiment”? Good question. Another question. Duno. Pilot study? For me the hole rho story is a mystery. And rather academic. Nobody is acting according to that theory. Not at least because the understanding of what value rho shoud have or how it could be estimated. Taking the greater sample size from the two estimations worked in the past. So what? Theoretically this would be the case if rho ~ 1 since then the combined power of the two TOST is the minimum of the individual powers. That would be my favoured candidate . Be warned: rho=1 throws an error in sampleN.2TOST() .— Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20180211 22:44 @ d_labes Posting: # 18401 Views: 10,278 

Dear Detlew, » » Another question: What is a “similar experiment”? » » Good question. Another question. Duno. Pilot study? » For me the hole rho story is a mystery. And rather academic. » Nobody is acting according to that theory. Not at least because the understanding of what value rho shoud have or how it could be estimated. » » Taking the greater sample size from the two estimations worked in the past. So what? » Theoretically this would be the case if rho ~ 1 since then the combined power of the two TOST is the minimum of the individual powers. That would be my favoured candidate . Yep. Slowly I get the impression it is a dead end. Below “within study rhos” aggregated by analyte. Within each study rho and its 95% CI was calculated. Then I calculated their medians (n is the number of studies), sorted by rho: analyte n med.rho med.lower med.upper Some results are crazy. ASA has a very low rho and its lower CL is negative… The extremes: Example of concordant outliers (poor metabolizers): » Be warned: rho=1 throws an error in sampleN.2TOST() .I know. Maybe:
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
nobody nothing 20180212 09:08 @ Helmut Posting: # 18403 Views: 10,096 

...maybe bring Clearance into the picture? — Kindest regards, nobody 
Astea ★ Russia, 20180211 17:34 (edited by Astea on 20180211 17:54) @ d_labes Posting: # 18397 Views: 10,202 

Dear Detlew! Thank you very much for the explanation! Now I've got it! (Yes, multitasks harm..) So, for ρ=0.8 I get now type1error.2TOST(CV=c(0.3, 0.25), n=122, theta1=c(0.8, 0.9), and inflation at 0.050024As I understand estimated from several datasets ρ is "between studies" ρ while in Power2TOST we need to use "within studies ρ". But it may be interesting while discussing multicomponent drugs. Especially question may arise for two components, when one of them is HVD while other is not and different approaches or CI limits involved (like telmisartan+amlodipine). The intermediate question is mentioned situation about parent drug and its metabolite  logically, the correlation for the parameters of parent drug and its metabolite should be stronger than for two different drugs tested on the same population? Dear Helmut! Do I understand correctly that in your latest code you exployed all AUC and Cmax individual data for each study in order to estimate "within rho"? — "We are such stuff as dreams are made on, and our little life, is rounded with a sleep" 
d_labes ★★★ Berlin, Germany, 20180211 19:36 @ Astea Posting: # 18400 Views: 10,173 

Dear Nasty! » So, for ρ=0.8 I get now » > type1error.2TOST(CV=c(0.3, 0.25), n=122, theta1=c(0.8, 0.9), » + theta2=c(1.25, 1/0.9), rho=0.8, details=TRUE) » and inflation at 0.050024 Don't forget, that type1error.2TOST() is based on simulations now. That's mainly because our (authors team of PowerTOST) brain is to small to derive an analytical solution. And simulations have an error. F.i. in setting the seed for the random number generator. type1error.2TOST(CV=c(0.3, 0.25), n=122, theta1=c(0.8, 0.9), theta2=c(1.25, 1/0.9), rho=0.8, setseed=F) In that light 0.050024 is of course not an alphainflation. As we know from theory, the IUT principle, the combination of two TOST via and assures alpha<=0.05. Thus interpret the result as 0.05. Full stop » As I understand estimated from several datasets ρ is "between studies" ρ while in Power2TOST we need to use "within studies ρ". I myself don't know what ρ or what value of ρ should be used. As I wrote above: It's under discussion now. Thus if you or somebody else have an opinion or arguments: Give it to me. — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20180211 22:48 @ Astea Posting: # 18402 Views: 10,197 

Dear Astea! » The intermediate question is mentioned situation about parent drug and its metabolite  logically, the correlation for the parameters of parent drug and its metabolite should be stronger than for two different drugs tested on the same population? Oh dear, yes! But that’s yet another story. » 1e+06 simulations. Time consumed (secs) » user system elapsed » 979.75 95.18 1115.72 Get a faster machine! My almost three years old tincan: 1e+06 simulations. Time consumed (secs) » Do I understand correctly that in your latest code you exployed all AUC and Cmax individual data for each study in order to estimate "within rho"? Yes. Apples and oranges. See there for a breakdown by analyte. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
ElMaestro ★★★ Belgium?, 20180211 18:43 @ Louis52 Posting: # 18398 Views: 10,170 

Hi all, can we take one step back and discuss what we are really trying to achieve here? Forget for a moment the famous theorems and equations and think practically. Ratios of Cmax and AUC are correlated within studies. No doubt about it. Increase Cmax and AUC increases, all other factors equal, and vice versa. It would perhaps be good if we could some model that via some rho so that we could calculate a slightly higher sample size to take into consideration that both ratios must pass the 80.00% 125.00% criterion. But I never heard a sponsor or CRO really express that need in a specific manner. I never saw a study failing on one metric and passing on the other and where someone afterwards thought she/he should have taken the correlation into consideration and all would have been good. Bear in mind also that both test and reference batches of any product have variation within and between. The latter is almost never explored but it is generally higher than within, as usual. Both, whether estimable/measurable or not, will be reflected in the rho we can observe and thus we may have to take that into consideration too. The exact same issue applies to the papers that try to express a general opinion about product A vs product C, when product A has been tested against product B, and B has been tested against C. It is a matter authors have managed to tiptoe elegantly around and certainly not something anyone wants to get mixed up in. What I mean here is I am in doubt if we are discussing a practical problem. And secondly if this problem is practical, I am wondering if the treatment we can realistically give the issue changes much given all the underlying complexity. — I could be wrong, but... Best regards, ElMaestro 
nobody nothing 20180212 09:10 @ ElMaestro Posting: # 18404 Views: 10,099 

General approach: problem > solution. Don't try to find nails everywhere, just 'cause you brought your hammer with you that day... — Kindest regards, nobody 
ElMaestro ★★★ Belgium?, 20180212 09:18 @ nobody Posting: # 18405 Views: 10,064 

Hi nobody, this reminds me of a quote I stumbled upon the other day, attributed to Paul Dirac who was known for being a stonecold scientist: "The aim of science is to make difficult things understandable in a simpler way; the aim of poetry is to state simple things in an incomprehensible way. The two are incompatible." — I could be wrong, but... Best regards, ElMaestro 
nobody nothing 20180212 09:38 @ ElMaestro Posting: # 18406 Views: 10,128 

Yeah, but both aim at new "fairy tales", new "lingual pictures", new parables, one side based on facts and numbers, the other side based on emotions. But where does the hammer come from? — Kindest regards, nobody 
Astea ★ Russia, 20180212 18:37 @ nobody Posting: # 18408 Views: 10,032 

Dear all! They say that upon hearing that one of his students had dropped out to study poetry David Hilbert said: "Good, he did not have enough imagination to become a mathematician". Dear Detleww! » In that light 0.050024 is of course not an alphainflation. As we know from theory, the IUT » principle, the combination of two TOST via and assures alpha<=0.05. Thus interpret the result as 0.05. Full stop Thank you very much for clarification! So then it's just a numeric atavism and misinterpretation. Dear Helmut! » Get a faster machine! I've got one, but currently my car do not provide calculations in PowerTost I may suppose there were some problems in your Acetylsalicylic acid study  may be in stability or inadequate sampling time, did you measure also salicylic acid? What was the dose? Below are my results on ASA study (data of reference drug only): rho is 0.667, 95% CI: [0.361; 0.844]. For Test+Ref data rho is about 0.755. — "We are such stuff as dreams are made on, and our little life, is rounded with a sleep" 
Helmut ★★★ Vienna, Austria, 20180213 01:37 @ Astea Posting: # 18409 Views: 9,997 

Dear Astea, may I call you Nasty as well? » I may suppose there were some problems in your Acetylsalicylic acid study  may be in stability… Samples put in an icebath until centrifugation, plasma diluted 1:1 with 5% ophosphoric acid for stabilization. » … or inadequate sampling time, Hhm. 00:05, 00:10, 00:15, 00:20, 00:30, 00:40, 00:50, 01:00, 01:20, 01:40, 02:00, 02:30, 03:00, 04:00, 06:00, 08:00, 10:00, 12:00 hours. No problems with "first point C_{max}". » … did you measure also salicylic acid? Sure. Nice rho (see in the list above). » What was the dose? 100 mg ASA (actually 5 × 20 mg tablets). I recalculated the entire study (October 1997!) from rawdata (nasty!). Maximum residual AUC in any of the 24 subjects 7%. CV_{intra}: ASA 18.3% (C_{max}), 11.8% (AUC_{0–t}); SA 9.58% (C_{max}), 8.71% (AUC_{0–t}). Both ASA and SA passed BE with flying colors. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Astea ★ Russia, 20180213 08:27 @ Helmut Posting: # 18410 Views: 10,074 

Dear Helmut! » I recalculated the entire study (October 1997!) from rawdata (nasty!). Very sorry about that! I didn't want to doubt into results of your study, just wanted to point out that the results of miscorrelation between Cmax and AUC should be more dependent on the features of the specific study than on the drug itself. » Maximum residual AUC in any of the 24 subjects 7%. Is it possible to expect large AUCresid for ASA when sampling time is 12 hours? » Hhm. 00:05, 00:10... That's perfect. But than may it be connected with fast elimination of ASA? That is sampling time is adequate but comparing to the less rapid drug the difference in 30 minutes in elimination phase could give sufficiently more error in calculating AUC (one day for jinn as thousand years for man)? The last question about it: what was the mean T1/2 (from these abrupt profiles I may suspect less than known in literature 20 minutes)? » may I call you Nasty as well? I would prefer Nastia (that was Nabokov who first pointed out the similar pronounciation) — "We are such stuff as dreams are made on, and our little life, is rounded with a sleep" 
Helmut ★★★ Vienna, Austria, 20180213 12:45 @ Astea Posting: # 18412 Views: 10,038 

Hi Nastia, » I didn't want to doubt into results of your study, No worries. I was curious myself. » just wanted to point out that the results of miscorrelation between Cmax and AUC should be more dependent on the features of the specific study than on the drug itself. Or the dose regimen (as Relaxation suspected)? » […] is sampling time is adequate but comparing to the less rapid drug the difference in 30 minutes in elimination phase could give sufficiently more error in calculating AUC (one day for jinn as thousand years for man)? » The last question about it: what was the mean T1/2 (from these abrupt profiles I may suspect less than known in literature 20 minutes)? Linear plot with enlarged time scale: Your wish is my command. Data cemetery: t_{lag} t_{max} t_{½} C_{max} AUC_{t} AUC_{ext} t_{lag}, t_{max} minutes; median (quartiles)t_{½ } minutes; harmonic mean (jackknife SD)C_{max } µg/mL; geometric mean (CV%)AUC_{t } h×µg/mL; geometric mean (CV%)AUC_{ext } 100(AUC_{t}–AUC_{∞})/AUC_{∞}; median (quartiles)— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Relaxation ★ Germany, 20180213 10:37 @ Helmut Posting: # 18411 Views: 10,000 

Dear All. Although I am lost regarding most of the mathematical discussion, I understood, that ASA seems to misbehave  and this information catched my exe. » 100 mg ASA (actually 5 × 20 mg tablets). To be very brief, from my experience, a study with multiple tablets under fasted conditions always could/might (will) result in an increase in variability in particular in Cmax. To visualize, imagine all tablets reach the stomach immediately, but every tablet has an individual chance to be emtyied into the intestine. So we might see subjects with one single peak (5 tablets at once) or subjects with 5 individual peaks (blurred together) and anything in between. These subjects will then show artificially low Cmax values that will not correlate at all. Looking at the individual profiles posted above I think I see at least a few "irregular profiles" even including late tmax at about 2 hours. I am not saying that this is a/the solution, but this may be one aspect helping to understand, why the correlation for ASA is lousy in comparison with other APIs and drug products. Just flashed through my mind. Best regards, Relaxation. 
Helmut ★★★ Vienna, Austria, 20180213 13:31 @ Relaxation Posting: # 18413 Views: 10,020 

Hi Relaxation, » Although I am lost regarding most of the mathematical discussion,… You are not alone. » … ASA seems to misbehave  and this information catched my exe. » » » 100 mg ASA (actually 5 × 20 mg tablets). I have to correct myself: 500 mg ASA (5 × 100 mg tablets; reference Bayer’s Aspirin^{®} 100 N). Don’t know why such a high dose was chosen (sponsor’s wish _{}); we had another analytical method sensitive enough for 100 mg as well. It is well known that at ~200 mg we are deep in saturation… » To be very brief, from my experience, a study with multiple tablets under fasted conditions always could/might (will) result in an increase in variability in particular in Cmax. » To visualize, imagine all tablets reach the stomach immediately, but every tablet has an individual chance to be emtyied into the intestine. » So we might see subjects with one single peak (5 tablets at once) or subjects with 5 individual peaks (blurred together) and anything in between. These subjects will then show artificially low Cmax values that will not correlate at all. You are absolutely right in general. Below simulations (n=24) with a lagtime of 1±1 h. Lagtimes simulated with a truncated normal distribution [0, 2]. V, k_{a}, CL simulated with a lognormal. CV_{intra} 12%, CV_{inter} 21%, GMR 100%. Single dose of 500 mg: AUC GMR (90% CI): 97.59% (74.93% – 127.11%) Single dose of five units à 100 mg: AUC GMR (90% CI): 98.96% (87.28% – 112.22%) As you rightly assumed, the intrasubject variability of C_{max} substantially increases (whereas the one of AUC decreases). » Looking at the individual profiles posted above I think I see at least a few "irregular profiles" even including late tmax at about 2 hours. See a more telling plot above. Latest t_{max} at 1:40. But: In 4/24 subjects t_{max} was >50 minutes (R) and in 6/24 (T). Too stupid to simulate that. » I am not saying that this is a/the solution, but this may be one aspect helping to understand, why the correlation for ASA is lousy in comparison with other APIs and drug products. Maybe. Maybe not. There are many examples very the variability in C_{max} is much higher than the one of AUC and the correlation is pretty good. Here both behave nicely (CV_{intra} 18.3% and 11.8%). Still fail to understand why I saw such a low correlation in my study (and Astea a much higher one in hers). — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 