jag009 ★★★ NJ, 20231206 05:19 (88 d 22:16 ago) Posting: # 23780 Views: 639 

Hi all, I have a question. What if my NCA calculated halflife of a drug is significantly longer than the literature reported halflife which is well established (and I have old study data to back up the literature halflife as well). The newly calculated halflife is longer because I sampled longer than usual and the bioanalytical method has a much lower BLQ. Note that the elimination phase also has a biphasic appearance. Since the data is the data, I assume there is nothing that I would need to do other than writing something to discuss why the my calculated halflife is longer? FYI, i just let Phoenix to pick the timepoints itself to calculate the halflife. Of course I can override and select the timepoint as well but then the R2 might not be optimal. Thx Jag 
Helmut ★★★ Vienna, Austria, 20231206 11:41 (88 d 15:54 ago) @ jag009 Posting: # 23782 Views: 589 

Hi John, ❝ What if my NCA calculated halflife of a drug is significantly longer than the literature reported halflife which is well established (and I have old study data to back up the literature halflife as well). The newly calculated halflife is longer because I sampled longer than usual and the bioanalytical method has a much lower BLQ. Note that the elimination phase also has a biphasic appearance. See this case (slides 16–21). A very old and ‘popular’ drug. ❝ Since the data is the data, I assume there is nothing that I would need to do other than writing something to discuss why the my calculated halflife is longer? Correct. No worries. ❝ FYI, i just let Phoenix to pick the timepoints itself to calculate the halflife. Of course I can override and select the timepoint as well but then the R2 might not be optimal. Define “optimal”. \(\small{R_{\text{adj}}^2}\) is just a tool and a “greedy” algorithm, since it might include too early time points. Further, it regularly fails with controlled release products (flat profiles) and multiphasic release products. Visual inspection of the fits is mandatory. In Phoenix I start with the ‘Best Fit’ algo and subsequently correct questionable start/end times. Yes, it is subjective but better than trusting in Artificial Unintelligence. See also there and scroll down a bit. It gives also some references. Heck, writing an article about estimating \(\small{\widehat{\mit{\lambda}}_\text{z}}\) is on my todolist for years… — 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 
jag009 ★★★ NJ, 20231206 16:46 (88 d 10:49 ago) @ Helmut Posting: # 23783 Views: 502 

Hi Helmut, ❝ See this case (slides 16–21). A very old and ‘popular’ drug. Thanks! The scenario on page 20 is exactly what I am facing but the difference in t1/2 is much larger than yours (i.e. 2.5 hrs vs 4.5 hrs). It's an IR product and the drug is very old. Previous studies (from archive or literature) had a profile with a monophasic elimination phase due to sampling time and BLQ. Since I sampled longer and has a much much lower BLQ, the biphasic appearance popped up. I double checked the bioanalytical method and I didn't see any issues (calibration curves looked great, intraday and interday CVs looked great, no other issues). ❝ ❝ FYI, i just let Phoenix to pick the timepoints itself to calculate the halflife. Of course I can override and select the timepoint as well but then the R2 might not be optimal. ❝ ❝ Define “optimal”. ❝ \(\small{R_{\text{adj}}^2}\) is just a tool and a “greedy” algorithm, since it might include too early time points. Further, it regularly fails with controlled release products (flat profiles) and multiphasic release products. Visual inspection of the fits is mandatory. In Phoenix I start with the ‘Best Fit’ algo and subsequently correct questionable start/end times. Yes, it is subjective but better than trusting in Artificial Unintelligence. Maybe R2 from PHX was like .99xxx and my R2 was like .7? PHX only picked timepoints along the "2nd phase" of the curve while I picked data from more timepoints from both the 1nd phase and the 2nd phase of the elimination phase. thx John 
Helmut ★★★ Vienna, Austria, 20231206 17:30 (88 d 10:05 ago) @ jag009 Posting: # 23784 Views: 526 

Hi John, ❝ ❝ See this case (slides 16–21). A very old and ‘popular’ drug. ❝ Thanks! The scenario on page 20 is exactly what I am facing but the difference in t1/2 is much larger than yours (i.e. 2.5 hrs vs 4.5 hrs). So? My drug had a half life of 2–3 hours acc. to the literature. With the proper estimation I got 4.63 ± 1.07 h (test) and 5.59 ± 1.19 h (reference). Which half lives were given in your case and which ones did you estimate? ❝ It's an IR product and the drug is very old. Paracetamol? ❝ ❝ ❝ FYI, i just let Phoenix to pick the timepoints itself to calculate the halflife. Of course I can override and select the timepoint as well but then the R2 might not be optimal. ❝ ❝ Define “optimal”. ❝ Maybe R2 from PHX was like .99xxx and my R2 was like .7? PHX only picked timepoints along the "2nd phase" of the curve … Makes sense. ❝ … while I picked data from more timepoints from both the 1nd phase and the 2nd phase of the elimination phase. Don’t. Then you are doing sumfink similar to the example in my slide 17. Even if not that extreme, you must not “mix” phases. It might well be that the second phase is not relevant. That’s why Harold Boxenbaum developed the concept of effective half life. In a nutshell: Fit a multicompartment model with hybrid constants (not volumes of distribution, and rate constants or clearances). $$C(t)=A_1\exp(\alpha_1)+A_2\exp(\alpha_2)+\ldots+A_n\exp(\alpha_n).$$ Then $$AUC_{0\infty}=\frac{A_1}{\alpha_1}+\frac{A_2}{\alpha_2}+\ldots+\frac{A_n}{\alpha_n}.$$ Assess the summands as fractions of \(\small{AUC_{0\infty}}\) and rank them in descending order. This gives you an idea, which one will be relevant in clinical practice, i.e., when you go to steady state. In many cases the slow phase(s) are not relevant at all. In my example, the first phase accounted for 98.3% of the \(\small{AUC_{0\infty}}\) and the second only 1.7%. — 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 
jag009 ★★★ NJ, 20231207 17:36 (87 d 09:59 ago) @ Helmut Posting: # 23788 Views: 484 

Hi Helmut, ❝ So? My drug had a half life of 2–3 hours acc. to the literature. ❝ With the proper estimation I got 4.63 ± 1.07 h (test) and 5.59 ± 1.19 h (reference). ❝ Which half lives were given in your case and which ones did you estimate? Halflife from literature is around 2 hours. t1/2 from my previous studies were around 23 hrs (w BLQ much much higher than my current studies). ❝ ❝ It's an IR product and the drug is very old. ❝ ❝ Paracetamol? Shhhh... ❝ ❝ … while I picked data from more timepoints from both the 1nd phase and the 2nd phase of the elimination phase. ❝ ❝ Don’t. Then you are doing sumfink similar to the example in my slide 17. Even if not that extreme, you must not “mix” phases. It might well be that the second phase is not relevant. That’s why Harold Boxenbaum developed the concept of effective half life. Understood. I was just goofing around to try and see what would happen to R2 if I just selected more timepoints. Thx J 