Imran ☆ Mumbai, 20070627 06:02 (5572 d 01:57 ago) Posting: # 835 Views: 24,294 

Dear PK Colleagues I have come across a problem while runing PK of steady state using WinNonline software. My queries are:
Thanking you in Anticipation Regards Dr.Imran Khan — Dr.Imran Khan 
Helmut ★★★ Vienna, Austria, 20070627 11:56 (5571 d 20:04 ago) @ Imran Posting: # 840 Views: 17,699 

Dear Imran! » 1. should trough concentrations and concentration of profiling day should » be run separately or in the same set of data to generate PK parameters?
Time deviations in steadystate data » 2. Should only trough values should be used for calculation of % fluctuation? %fluctutation (or %PeaktoTrough Fluctuation, %PTF) is defined as: \(\small{\%PTF=100\frac{C_{\textrm{max}}C_{\textrm{min}}}{C_{\textrm{av}}}}\) where \(\small{C_{\textrm{av}}=AUC_{\tau}/\tau}\), and \(\small{C_{\textrm{max}}}\), \(\small{C_{\textrm{min}}}\) refer to extremes of the profile in steady state. In WinNonlin you have to calculate %PTF manually (it's not given in the result workbook). — Diftor heh smusma 🖖 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Imran ☆ Mumbai, 20070629 05:13 (5570 d 02:47 ago) (edited by Jaime_R on 20070629 10:01) @ Helmut Posting: # 844 Views: 17,663 

Dear HS Thanks for ur mail and valuable suggestion on the issue. I data I want to estimate for SS study is given below.
Subject Period Trough sample Profiling till 72.00 hrs The step I followed calculation of PK Parameters is as: PK/PD/NCA Analysis Wizard , noncompartment modeling, select model 200, data variables, dosage regimen and selecting steady state followed by modeling, generation of PK output. The XL file I have attached, the data processed is excluding trough sample (day1, 5, 6 and 7), should I process trough data and profiling data separately. As u wrote in ur mail that in WinNonlin %PTF to be calculate manually, but here in my case I calculated all of the primary and secondary parameters (Excel file attached). I have troubleshooting how the data to be presented in the WinNonline, I tried in all the possible way, but I am not sure about the output. Primary Efficacy Parameters: Cmin, Cmax, AUC0   Secondary Efficacy Parameters: Tmax, % Fluctuation Please suggest. Regards Dr.Imran Khan — Dr.Imran Khan 
Jaime_R ★★ Barcelona, 20070629 10:29 (5569 d 21:31 ago) @ Imran Posting: # 845 Views: 17,413 

Dear Imran, I edited your post (took me half an hour), because it came out as a mess. Please use the 'Preview'button before posting (and read the section about formating in the Forum's Policy). Don't use <tabs>, use [ code]with blanks between columns[/code] instead. » The XL file I have attached [...] What's 'XL'? Do you mean Micro$oft's Excel? Although the Forum's software supports Uploads, this function is deactivated. Attachments are not possible anyhow (this is not an email list). » [...] (Excel file attached). OK, I was right, but just out of couriosity: what did you actually try, to 'attach a file'? » I have troubleshooting how the data to be presented in the WinNonline, I tried in all the possible way, but I am not sure about the output. Why don't you contact Pharsight's Support? » Primary Efficacy Parameters: [...] AUC0   '#61556' is in the private code range of UTF8. No greek letters, Unicode, or ISO8859 above DEC 255 are supported. You would have noticed this during Preview. Maybe you mean the greek letter 'tau' denoting a dosage interval (Unicode #964). Don't take it personally, but I think the Forum should not become a Fastfood Restaurant (quickanddirty). — Regards, Jaime 
Imran ☆ Mumbai, 20070630 12:50 (5568 d 19:10 ago) (edited by Jaime_R on 20070630 13:22) @ Jaime_R Posting: # 848 Views: 17,385 

Dear Jaime Extremely sorry! I tried to send the data in best possible way, even checked the preview, but I could not trace attachement option in the mail I have definately wrote a mail to Pharsight, but as a matter of discussion I wrote to Forum. Even I am agree that the Forum should not become a Fastfood Restaurant Best Regards, Imran  Edit: Full quote removed. [Jaime] 
Jaime_R ★★ Barcelona, 20070630 13:33 (5568 d 18:26 ago) @ Imran Posting: # 849 Views: 17,298 

Dear Imran! » Extremely sorry! OK, my reaction was also a little bit too harsh... » [...] but I could not trace attachement option in the mail Yes, because this is not a Mailing List, but a Forum. File uploads may be possible in the new version. » I have definately wrote a mail to Pharsight,[...] Expect an 'RTFM'... » [...] but as a matter of discussion I wrote to Forum. Yes, that's fine! — Regards, Jaime 
Helmut ★★★ Vienna, Austria, 20070629 21:08 (5569 d 10:51 ago) @ Imran Posting: # 847 Views: 17,704 

Dear Imran! » The step I followed calculation of PK Parameters is as: PK/PD/NCA Analysis Wizard , noncompartment modeling, select model 200, data variables, dosage regimen and selecting steady state followed by modeling, generation of PK output. Yes fine, but the order in Dosage Regimen is: [x] Steady state Dose Time of Last Dose Tau » The XL file I have attached, the data processed is excluding trough sample (day1, 5, 6 and 7), [...] Sure, you are interested in the profile (WinNonlin simply ignores the saturation phase, which is fine). » should I process trough data and profiling data separately. In versions 5.1+ you may run a linear regression of e.g., the last three trough values to check whether you have reached steady state (95% CI of the slope should include zero). Model 502 (Linear) of example's data below give: Last 4 troughs (24 h  96 h): slope 0.063, CI 0.049, +0.176 Last 3 troughs (48 h  96 h): slope 0.019, CI 0.120, +0.158 ...so you may assume steady state conditions. » As u wrote in ur mail that in WinNonlin %PTF to be calculate manually, but here in my case I calculated all of the primary and secondary parameters [...] Oh, you are right! » I have troubleshooting how the data to be presented in the WinNonline, I tried in all the possible way, but I am not sure about the output. Why don't you keep it simple and check the results manually? OK, I've done that for you... D=100, V/F=1, k01=0.6931, k10=0.06931, tau=24h for five days gives (rounded to 1 decimal place): time conc Now let's have a look at the output (NonTransposed Final Parameters Tab), and a 'manual' calculation WinNonlin5.2 'manual' Fine. Please note, that AUClast = AUCtau = AUCall. Generally nobody is interested in the sampling beyond the last administration + tau, but in your case obviously this was the case (+72 hours). If we add two more samples (144 h, 168 h), WinNonlin's output might get a little bit confusing for a novice, since: time conc WinNonlin5.2 'manual' WinNonlin is 'clever' enough to keep AUCtau (and therefore Cav, and %Fluctuation correct within tau), but please note AUClast # AUCtau and AUCall! If we sample for another 48 hours until we get a BLQ: time conc WinNonlin5.2 'manual' Now finally we ran into AUClast # AUCtau # AUCall! AUCall adds a triangle from the Tlast to the next sampling time point, assuming C=0. If you know of any serious reference using AUCall, please tell me. It's Pharsight's invention and IMHO useless  I removed it from my templates... It's also funny that Pharsight's business rival Thermo_{Scientific} added this 'metric' to Kinetica as well. In short:
» Primary Efficacy Parameters: Cmin, Cmax, AUC0   » Secondary Efficacy Parameters: Tmax, % Fluctuation In BA/BE we should not talk about Efficacy... — Diftor heh smusma 🖖 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Imran ☆ Mumbai, 20070802 13:52 (5535 d 18:07 ago) @ Helmut Posting: # 957 Views: 17,275 

Dear HS Thanks for the solutions. I worked with WinNonlin and I am through with my results. One more Issue I would like to discuss with u. How can we calculate or prove that SS is achieved. I had used SAS for the same by repeated measures of ANOVA for Cpd calculation, and withdrawn the conclusion based on time* formulation interaction (p value.) What procedure to be followed by using Winnonlin 5.0.1. or any other suitable method can be used to prove SS is achived. Pls comment. Best Regards Dr.Imran  Edit: Full quote removed. Please see this post! [HS] — Dr.Imran Khan 
Helmut ★★★ Vienna, Austria, 20070802 15:07 (5535 d 16:53 ago) @ Imran Posting: # 958 Views: 17,339 

Dear Imran! » How can we calculate or prove that SS is achieved. » I had used SAS for the same by repeated measures of ANOVA for Cpd calculation, and withdrawn the conclusion based on time* formulation interaction (p value.) In never understood this procedure. OK, statistically yes, but would you really throw away an entire study based on such a result? I always preferred it to look at the time course of the subjects and eventually exclude only ones who were not in steady state on the profile day. Of course you have to state this procedure in the protocol. » What procedure to be followed by using Winnonlin 5.0.1. or any other suitable method can be used to prove SS is achived. For my personal suggestions see this tread. If you want to perform the analogue of SAS' repeated measures ANOVA, you will have to fight yourself through WinNonlin's Linear Mixed Effects Modeling feature  and if you succeed, come back and tell us how you did it! — Diftor heh smusma 🖖 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Imran ☆ Mumbai, 20070806 11:48 (5531 d 20:12 ago) (edited by Jaime_R on 20070806 12:24) @ Helmut Posting: # 965 Views: 17,372 

Dear HS and Colleagues Hi! In SS study Cpd Analysis should we calculate SS acheived for each subject, or it should be calulated as a mean of all observation. What if a subject 'A' has not acheived SS, sholud the subject be included in the PK analysis. I understand we calculate ABE, but would be it questioned if any subject is not in SS state. Please comment on the issue. Best regards Dr.Imran  Edit: Full quote removed. Please see this post! [Jaime] — Dr.Imran Khan 
Helmut ★★★ Vienna, Austria, 20070806 22:16 (5531 d 09:44 ago) @ Imran Posting: # 966 Views: 17,499 

Dear Imran! » In SS study Cpd Analysis should we calculate SS acheived for each subject, or it should be calulated as a mean of all observation. As already told in this thread, my personal preferences are always to assess achievement of SS for individual subjects. » What if a subject 'A' has not acheived SS, sholud the subject be included in the PK analysis. IMHO this subject should be excluded, because if the subject was not in steady state, the superposition principle of pharmacokinetics is not fulfilled. You may only make valid statements (about accumulation, etc.) if AUCinf (single dose) = AUCtau (steady state). » I understand we calculate ABE, but would be it questioned if any subject is not in SS state. At least I would do so! — Diftor heh smusma 🖖 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
KR ★ India, 20090413 14:34 (4915 d 17:25 ago) (edited by Ohlbe on 20090413 22:30) @ Helmut Posting: # 3516 Views: 16,069 

Dear Helmut, Adding to that, if dosing interval for reference product is 24 hours and that of test product is 12 hours i.e. tau=24 hrs. for reference and tau=12 hrs. for test product then how can we calculate AUCtau ? means if we put tau=12 hrs. for test product in the model then which AUC area will be estimated by WinNonlin i.e first 012 hrs or last 012 hrs ? Moreover, if we calculate AUC024 for both test and reference in above case then how WinNonlin calculates ? Should i give common dosing interval i.e. tau=24 hrs. for both test and reference products and how much AUC024 calculation is reliable for test product? Thanks and regards, KR  Edit: Full quote removed. Please see this post! [Ohlbe] 
vixen ☆ Czechia, 20200427 10:10 (883 d 21:49 ago) @ Helmut Posting: # 21350 Views: 5,811 

Hello, I like Helmut's suggestion to assess achievement of SS for individual subjects. I wonder though whether I should evaluate the Cpds on a normal or logarithmic scale. What is your approach? Thanks, vixen 
Helmut ★★★ Vienna, Austria, 20200427 11:45 (883 d 20:15 ago) @ vixen Posting: # 21351 Views: 5,808 

Hi vixen, » I like Helmut's suggestion to assess achievement of SS for individual subjects. My suggestion dates back to 2007. A while ago… I don’t use it since 2010 and don’t recommend it any more (see this presentation, slide 14). Furthermore, the EMA stated:* A specific statistical method to assure that steady state has been reached is not considered necessary in bioequivalence studies. Descriptive data is sufficient. » I wonder though whether I should evaluate the Cpds on a normal or logarithmic scale. Normal – otherwise you cannot deal with BQLs and missings. » What is your approach? See the presentation.
— Diftor heh smusma 🖖 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 