Bioequivalence and Bioavailability Forum • Scaling of Cmin

Scaling of Cmin [Regulatives / Guidelines]

posted by VStus – Poland, 2017-02-03 14:04 (2638 d 02:53 ago) – Posting: # 17005
Views: 10,790
(edited by VStus on 2017-02-03 15:50)

Dear Helmut,

Have you solved this puzzle?

I must confess that Liu's article is too hard for me. I understand that the idea of scaling is based on assessment of within-subject variability after the administration of only Reference formulation.

But article is targeting repeated crossover studies (RRTT|TTRR) for assessment of population/individual bioequivalence. Due to this, a more complicated statistical model was proposed and justified. But we are not interested in population bioequivalence now.

Would it be correct to analyze only a reference subset of data to estimate the variability of reference PK parameter only? Let's assume I'm interested only in possibility of widening of acceptance limits for Ctau_ss, do I need test formulation data at all?

We will not have different formulations in resulting subset, just factors of period + sequence + subject + repetition.

I have reduced Liu's dataset to have:
subject - 20 levels (1-20)
sequence - 2 levels (RT and TR)
period - 2 levels (1 or 2)
repetition - 2 levels (1 or 2)
AUC for Reference formulation.

Which gives me:


anova(lm(log(AUC) ~ prd + seq + rep + subj:seq, data=data, na.action=na.exclude))

## Residuals 19 0.60602 0.031896 

100*sqrt(exp(0.031896)-1)

## [1] 18.00281

Residual MS is higher than reported by Lui for Reference formulation ('MS(R) = 0.03094'), thus it seems that I'm overestimating the variability of the Reference in this simplified model.

Thank you very much in advance!

Regards, VStus

Sorry for confusion: this is not a replicate design

Complete thread:

Type of study in modified release formulation EMEA Compliance 2014-03-13 09:43 [Regulatives / Guidelines]
- Type of study in modified release formulation EMEA nobody 2014-03-13 09:52
- Type of study in modified release formulation EMEA fno 2014-03-13 11:16
  - Type of study in modified release formulation EMEA kumarnaidu 2014-11-27 11:02
    - Type of study in modified release formulation EMEA nobody 2014-11-27 11:37
      - Type of study in modified release formulation EMEA kumarnaidu 2014-11-27 12:53
        
        Scaling of Cmin Helmut 2014-11-27 13:47
        
        Scaling of Cmin kumarnaidu 2014-11-27 15:12
        Scaling of Cmin kumarnaidu 2014-12-05 06:03
        
        Steady state kumarnaidu 2014-12-10 11:15
        
        Steady state nobody 2014-12-10 17:04
        
        Scaling of Cmin Dr_Dan 2014-12-10 17:21
        
        Scaling of Cmin Helmut 2014-12-10 18:40
        
        Scaling of Cmin d_labes 2014-12-11 13:09
        
        Scaling of Cmin Helmut 2014-12-11 14:53
        
        Scaling of CminVStus 2017-02-03 13:04
        
        Scaling of Cmin zizou 2017-02-03 13:49
        
        Scaling of Cmin VStus 2017-02-03 15:37
        Scaling of Cmin VStus 2017-02-06 08:55