arl_stat ★ India, 20210731 09:42 (1139 d 20:41 ago) Posting: # 22489 Views: 5,321 

Hello everyone. Hope all are safe in this Pandemic situation. The query is regarding achievement of Steady state using NOSTASOT (NonStatisticalsignificance–ofTrend) method. Please help me out for SAS codes for analysis. Thank you so much. Edit: Category changed; see also this post #1. [Helmut] 
Helmut ★★★ Vienna, Austria, 20210731 12:58 (1139 d 17:25 ago) @ arl_stat Posting: # 22490 Views: 4,585 

Hi arl_stat, ❝ […] achievement of Steady state using NOSTASOT (NonStatisticalsignificance–ofTrend) method. Never heard of this abbreviation. THX for the explanation. ❝ Please help me out for SAS codes for analysis. Sorry, I’m not equipped with ‘’. Easy in any software. Run a linear regression of predose concentrations vs time and test the slope against zero (or whether zero is included in the 95% CI of the slope). The former should be part of the output. However, I don’t recommend it (see here and there). The EMA stated:* Achievement of steady state can be evaluated by collecting predose samples on the day before the PK assessment day and on the PK assessment day. A specific statistical method to assure that steady state has been reached is not considered necessary in bioequivalence studies. Descriptive data is sufficient.
Simulated onecompartment model: V = 4, D = 500, k_{01} = 0.6931472 h^{–1}, k_{10} = 0.0504107 h^{–1}, τ = 24. Sufficient builtup of (pseudo) state state: 96 h = 6.98 half lives.
— 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 
Ben ★ 20210805 10:08 (1134 d 20:16 ago) @ Helmut Posting: # 22509 Views: 4,446 

Hi Helmut, ❝ Run a linear regression of predose concentrations vs time and test the slope against zero (or whether zero is included in the 95% CI of the slope). The former should be part of the output. ❝ However, I don’t recommend it (see here and there). So you are essentially saying statistical relevance is not the right tool here. Agreed. Instead of relying on visual inspection & gut feeling (= common sense? ) can we define pharmacological relevance? Is there a way to define quantitative thresholds based on the PK (or even PD?) of the compound (i.e. concentration should not change by more than x%)? Best regards, Ben. 
Helmut ★★★ Vienna, Austria, 20210805 13:43 (1134 d 16:41 ago) @ Ben Posting: # 22511 Views: 4,309 

Hi Ben, ❝ So you are essentially saying statistical relevance is not the right tool here. Agreed. I was talking about statistical significance. When it comes to a test, see the end of Section 1 in this post (EUFEPS workshop, Bonn, June 2013). ❝ Instead of relying on visual inspection & gut feeling (= common sense? ) … Well, we are using visual inspection in other areas as well. Automatic algos for selecting time points in estimating \(\small{\hat\lambda_z}\) (e.g., \(\small{R_{\textrm{adj,max}}^{2}}\), \(\small{AIC_\textrm{min}}\), \(\small{\text{TTT}}\)) quite often fail for ‘flat’ profiles (MR) or multiphasic profiles. I’m fine with selecting time points ‘manually’. Never had any problems with acceptance. ❝ … can we define pharmacological relevance? That’s actually the idea behind assessing the slope. Either we are still in the saturation phase (slope >0) or reasonably close to true steady state (slope ≈0). ❝ Is there a way to define quantitative thresholds based on the PK (or even PD?) of the compound (i.e. concentration should not change by more than x%)? Radio Yerevan answers: Based on PK, in principle yes. But how could we do that? We design the study based on τ and t_{½}. Hopefully we don’t use an average t_{½} – from the literature – but a worst case (i.e., a longer one). $$C_\tau$$$$\small{ \begin{array}{crr} \hline \text{Dose} & \text{% of steady state} & \text{% Change} \\ \hline 1 & 50.00000 &  \\ 2 & 75.00000 & 50.000000 \\ 3 & 87.50000 & 16.666667 \\ 4 & 93.75000 & 7.142857 \\ 5 & 96.87500 & 3.333333 \\ 6 & 98.43750 & 1.612903 \\ 7 & 99.21875 & 0.793651 \\ \hline \end{array}}$$Looks nice on paper. However, I see a problem here (maybe I’m wrong). In the regression we assess the last three predose concentrations, which – to some extent – takes the interoccasion variability into account. Of course, we may fall into the trap mentioned previously. When we set a threshold of \(\small{x\%}\), we are essentially believing that the last two predose concentrations are the true ones, right? Of course, that’s another trap. — 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 
Ben ★ 20211017 14:16 (1061 d 16:08 ago) @ Helmut Posting: # 22630 Views: 3,271 

Hi Helmut, I forgot to answer... ❝ When it comes to a test, see the end of Section 1 in this post (EUFEPS workshop, Bonn, June 2013). Thanks, I more and more come to the same conclusion... ❝ ❝ Is there a way to define quantitative thresholds based on the PK (or even PD?) of the compound (i.e. concentration should not change by more than x%)? ❝ ... In the regression we assess the last three predose concentrations, which – to some extent – takes the interoccasion variability into account. Of course, we may fall into the trap mentioned previously. I was thinking about the following: When we do a linear regression log(y) = a*x + b (+ eps), then the interpretation of a is that when x changes by 1 unit, then y changes (on average) by (exp(a)  1) * 100%. That means we can make a statement about %change in predose concentration and we could maybe set relevance limits for this change. But the trap that you mentioned is I guess still valid and does not go away (we may argue not with the estimated coefficient of a but with some upper CI/PI limit (e.g. 68%), but nevertheless the issue remains). ❝ When we set a threshold of \(\small{x\%}\), we are essentially believing that the last two predose concentrations are the true ones, right? Of course, that’s another trap. Yes, agreed. One more question: In your lecture you state that one should calculate gMean as well. Are you also calculating gMean ratios, i.e. calculating point estimates for the comparison of different time points (e.g. each vs. last)? Best regards, Ben. 
Helmut ★★★ Vienna, Austria, 20211020 14:36 (1058 d 15:48 ago) @ Ben Posting: # 22646 Views: 3,201 

Hi Ben, ❝ In your lecture you state that one should calculate gMean as well. This was suggested at numerous conferences and I’m reporting it for ~ten years. ❝ Are you also calculating gMean ratios, i.e. calculating point estimates for the comparison of different time points (e.g. each vs. last)? No. Just a simple table like $$\small{\begin{array}{rcc} \text{time} & \overline{\textrm{T}}_\textrm{geom.}\;(\text{CV}\;\%) & \overline{\textrm{R}}_\textrm{geom.}\;(\text{CV}\;\%)\\\hline 2\,\tau & 19.9\;(16.4) & 20.9\;(26.4)\\ \tau & 20.1\;(25.3) & 21.2\;(13.6)\\ \pm0 & 20.3\;(26.1) & 21.4\;(14.7)\\ \tau & 20.3\;(18.6) & 21.3\;(31.2)\\\hline \end{array}}$$ — 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 