Bioequivalence and Bioavailability Forum

Baseline; another example [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2015-09-18 19:16 (3141 d 23:34 ago) – Posting: # 15431
Views: 19,171

Dear Ohlbe,

another example explaining the method outlined in this post.
There might not only be circadian fluctuations in the baseline but others with a lower frequency super­imposed. The BL [12–25] consists of [10–20] within the day and [2–5] within a 28-days cycle. Let’s explore a four-period study:



Fat lines are the pre-dose profiles to be sampled prior to administrations in each period according to the EMA’s GL.

What happens if we subtract these values from the the ones on the following days? I plotted the dif­fe­rences (ignoring the if-negative-set-to-zero rule).



There will be small biases because the GL’s method assumes that baselines on dosing days are es­sen­ti­ally identical to the ones before. The largest absolute bias is observed in periods 1 and 3 because we are close to the inflection points of the 28-days cycle. Less bias in periods 2 and 4 (close to the max­i­mum and minimum).

The alternative method. Sampling only one baseline before period 1 and adjusting for the predose value in each period.



Not so nice. However, think about the doubled sampling volume in the GL’s method…

Let’s dose! Identical BA in all periods (the true C_max 2.75 times the maximum baseline). What we would observe (periods stacked):



First the GL’s method:



Next the alternative:



Practically superimposible profiles, methods almost indistinguishible.
Bias (expressed as %RE). GL = 1, alternative = 2:

method     1     2      1     2  
period       AUCt         Cmax    
  1      +0.97 +0.04  +0.48 -0.07
  2      -0.22 -0.40  -0.07 -0.35
  3      -0.96 -1.03  -0.48 -0.03
  4      +0.22 -0.60  +0.07 +0.25

I can live with it; especially given that with the alternative method one needs 37.5% less blood samples.

—
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

Complete thread:

• Baseline correction vs non-baseline cor­rection jag009 2015-09-15 20:29 [Regulatives / Guidelines] 
  • Baseline correction vs non-baseline correction Lucas 2015-09-16 14:16
    • Baseline correction vs non-baseline correction Relaxation 2015-09-18 10:25
  • Baseline correction or supra-thera­peu­tic dose Helmut 2015-09-16 15:16
    • Baseline correction or supra-thera­peu­tic dose Ohlbe 2015-09-16 17:55
      • Baseline profile prior to each period? Helmut 2015-09-16 18:15
      • Baseline correction examples Helmut 2015-09-17 15:44
        • Baseline correction examples Lucas 2015-09-18 14:19
          • Baseline correction examples Helmut 2015-09-18 17:28
            • Baseline correction examples Mauricio Sampaio 2016-02-07 03:05
              • Baseline correction examples Lucas 2016-02-10 11:48
                • Postmenopausal women Helmut 2016-02-10 12:26
                • Baseline correction examples Mauricio Sampaio 2016-02-11 01:38
                • Baseline correction examples Dr_Dan 2016-02-11 09:22
                  • Postmenopausal women Mauricio Sampaio 2016-02-12 03:24
                    • Postmenopausal women Dr_Dan 2016-02-15 17:45
      • Baseline; another exampleHelmut 2015-09-18 17:16
        • Baseline; another example nobody 2016-02-12 09:10
          • Baseline; another example Helmut 2016-02-12 13:37
            • Baseline; another example nobody 2016-02-12 14:08
              • Slowly going OT: BE study simulations Helmut 2016-02-12 15:47
                • Slowly going OT: BE study simulations nobody 2016-02-12 16:15
                  • Religious debate Helmut 2016-02-12 17:04
                    • Religious debate nobody 2016-02-12 17:26
                      • Religious debate ElMaestro 2016-02-13 12:53
                        • Religious debate nobody 2016-02-14 15:23
                • Slowly going OT: BE study simulations Ohlbe 2016-02-13 13:10
                  • Slowly going OT: BE study simulations Helmut 2016-02-13 15:02
                    • Slowly going OT: BE study simulations lizhao 2016-02-25 17:31
                      • Business as usual Helmut 2016-02-25 17:44
                        • Business as usual lizhao 2016-02-25 17:59