Bioequivalence and Bioavailability Forum

Setup in Phoenix/WinNonlin [Study Assessment]

posted by Helmut – Vienna, Austria, 2016-05-14 04:26 (2897 d 20:49 ago) – Posting: # 16302
Views: 31,386

Hi Angus,

❝ It is a very well known drug and many MR formulations are on the market. (You have experience with this drug).

If we are talking about the same goody: Watch out for polymorphism… Sometimes you have poor metabolizers in the study where enzymes get saturated at higher doses. In one subject I once got a slope of 1.54 for AUC and 2.16 for C_max over a only twofold dose range! For the other subjects it got 1.05 and 1.02 with a very narrow CI.

❝ There are only two does levels to plot. The relationship is as follows:

❝

❝ LnPK=B0+B1*Ln(dose) where LnPK pertains to Cmax or AUC.

❝

❝ So we have a regression line going through the points: we evaluate the slope (B1), intercept

OK, so far.

❝ and the confidence intervals about the slope to evaluate dose proportionality.

This is beyond me. df = n – p where n is the number of data points and p the number of parameters. How can you calculate a CI with df = 0?

❝ Brian Smith in Pharm Research year 2000 has extended the approach from the original UK working party.

Yep. Smith et al. use a mixed-effects model, where subjects are a random effect. Thus we increase n. Now a CI is possible even for p = 2.

❝ It seems that you can calculate intrasubject and intersubject variance e.g. for AUC and partial AUC from this approach.

Correct.

❝ I do not follow how to do it. I use the usual intrasubject and intersubject values from Phoenix WinNonlin 6.4 and I am happy with that.

If you are happy with that, what is your question? :-D

If you want to reproduce Smith’s results in Phoenix/WinNonlin: Start with a worksheet (columns subject, dose, Cmax, AUC, whatsoever). log-transform: dose, Cmax, … and weight=1/logCmax, … Send to LME. Map Subject as Classification, logCmax as Rgeressor, and logCmax as Dependent.
Model Specification: logCmax
Fixed Effects Confidence Level: 90%
Variance Structure / Random 1: Subject
With Smith’s C_max-data of Table 1 I got for the slope:
0.7617 (90% CI: 0.6696, 0.8539), slightly different from the reported 0.7615 (0.679, 0.844). Why? Duno.

[image]
(jitter added to doses)

See also chapter 18.3 in Chow/Liu. Without explanation they recommend a 95% CI but a 90% CI in elaborating Smith’s approach. In general I prefer a weighted model (hence the transformation above). Fits much better.

                 SSQ      AIC   Var(Subject)  Var(Res)

w = 1          0.07389   9.247     0.1120     0.01456 

w = 1/logCmax  0.01548  -8.917     0.1108     0.003076

PS: Can you ask “the other worker” why he/she calculated the 98% CI?

—
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Helmut Schütz

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Science Quotes

Complete thread:

Dose Proportionality and Variance AngusMcLean 2016-05-11 16:55
- More information, please Helmut 2016-05-12 14:34
  - More information, please AngusMcLean 2016-05-13 16:40
    - Setup in Phoenix/WinNonlinHelmut 2016-05-14 02:26
      - Setup in Phoenix/WinNonlin AngusMcLean 2016-05-14 18:54
        
        Setup in Phoenix/WinNonlin Helmut 2016-05-15 14:47
        
        Setup in Phoenix/WinNonlin AngusMcLean 2016-05-15 15:17
        
        Phoenix 64 Warning Helmut 2016-05-15 15:56
        
        Phoenix 64 Warning AngusMcLean 2016-05-15 20:11
        
        OT: imperial vs. metric units Helmut 2016-05-16 16:26
        
        Setup in Phoenix/WinNonlin ElMaestro 2016-05-15 20:54
        
        Setup in Phoenix/WinNonlin AngusMcLean 2016-05-15 22:30
      - Setup in Phoenix/WinNonlin AngusMcLean 2016-05-16 21:00
        
        NCSS vs. PHX/WNL vs. SAS Helmut 2016-05-17 01:50
        
        NCSS vs. PHX/WNL vs. SAS - Validation? mittyri 2016-05-18 08:23
        
        Diagnostics ElMaestro 2016-05-18 09:20
        
        Diagnostics: R and Phoenix Helmut 2016-05-18 15:14
        
        Diagnostics: R zizou 2016-05-22 19:07
        
        Diagnostics: R Helmut 2016-05-23 01:22
        
        SASian potpourri d_labes 2016-05-24 12:02
        
        Compilation Helmut 2016-05-24 14:27
        
        REML or not d_labes 2016-05-24 16:33
        
        complete or not Helmut 2016-05-24 16:57
        
        Compilation AngusMcLean 2016-05-26 16:46
        
        doubts about NCSS Helmut 2016-05-26 19:13
        
        Doubts about NCSS zizou 2016-05-26 23:38
        
        Compilation AngusMcLean 2016-05-28 00:51
        
        Kenward-Roger? Helmut 2016-05-28 15:59
        
        90% confidence interval for R_dnm Shuanghe 2019-01-04 17:45
        
        90% confidence interval for R_dnm d_labes 2019-01-05 14:01
        
        Visualizing lmer and limits mittyri 2019-01-06 17:00
        
        Visualizing lmer and limits Shuanghe 2019-01-07 11:05
        Visualizing lmer and limits d_labes 2019-01-07 15:08
        
        Visualizing lmer and limits mittyri 2019-01-13 23:53
        
        90% confidence interval for R_dnm Shuanghe 2019-01-07 10:53
        
        90% confidence interval for R_dnm d_labes 2019-01-07 15:17
        
        90% confidence interval for R_dnm Shuanghe 2019-01-07 17:11
        
        90% confidence interval for R_dnm d_labes 2019-01-07 18:24
        offtop: greek letters and tables mittyri 2019-01-08 00:19
        
        OT: greek letters and symbols Helmut 2019-02-02 16:04
        
        Smith’s paper Helmut 2016-05-18 14:44
        
        Smith’s paper d_labes 2019-01-05 15:00

Setup in Phoenix/WinNonlin [Study As­sess­ment]

Complete thread:

Setup in Phoenix/WinNonlin [Study Assessment]