yjlee168 Senior Kaohsiung, Taiwan, 20090714 14:16 Posting: # 3954 Views: 8,707 

Dear All, I just like to know if it is reasonable to estimate lambda_{z} when doing data analysis of a multipledosed steadystate (SS) BE/BA study. It is because we just collect the plasma/blood sample within one dosing interval (Tau) at steadystate in a multipledosed BE/BA study. It looks like there is no such terminal phase at all in multipledosed BE/BA study. If it is not reasonable, is there any way to estimate the elimination rate constant (k_{el}), halflife, V_{ss} or the accumulation index? In WinNonlin v5.x, lambda_{z} still needs to be estimated first for further calculations of other NCA parameters. Thanks in advanced. — All the best, Yungjin Lee bear v2.8.31: created by Hsinya Lee & Yungjin Lee Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear Download link (updated) > here 
Helmut Hero Vienna, Austria, 20090715 15:09 @ yjlee168 Posting: # 3955 Views: 7,317 

Dear Hsinya & Yungji! » I just like to know if it is reasonable to estimate lambda_{z} when doing data analysis of a multipledosed steadystate (SS) BE/BA study. Good question! » It is because we just collect the plasma/blood sample within one dosing interval (Tau) at steadystate in a multipledosed BE/BA study. Most people would do so – although I’ve seen others who took samples after τ. » It looks like there is no such terminal phase at all in multipledosed BE/BA study. We should be cautious in using ‘terminal phase’ – especially in NCA. Personally I prefer ‘apparent elimination’ or the like to express that I’m not dealing with a particular PK model. » If it is not reasonable,… In steady state within τ you may get a value similar to SD, but with noisy data – and if more than one compartment is needed to describe the PK – most likely not. Think about a twocompartment model with accumulation due to the ‘deep’ compartment. In SD you would only catch the first one (you think it’s elimination, but in ‘reality’ it’s only distribution). In steady state the second one becomes visible. » … is there any way to estimate the elimination rate constant (k_{el}), halflife, V_{ss} or the accumulation index? Tricky.
» In WinNonlin v5.x, lambda_{z} still needs to be estimated first for further calculations of other NCA parameters. That’s rubbish. WinNonlin uses
which needs
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
yjlee168 Senior Kaohsiung, Taiwan, 20090716 11:53 (edited by yjlee168 on 20090716 12:06) @ Helmut Posting: # 3957 Views: 7,208 

Dear Helmut, Thank you for your messages. » Most people would do so – although I’ve seen others who took samples after τ. For what purpose to take blood sample after tau? Is it worth to do so? » We should be cautious in using ‘terminal phase’ – especially in NCA. Personally I prefer ‘apparent elimination’ [...] Absolutely agree. » In steady state within τ you may get a value similar to SD, but with noisy data – and if more than one compartment is needed to describe [...] So, it looks like that no lambda_{z}, no NCA... » Tricky. I would not try to play around with elimination from steady state within tau. It is inevitable for us in Taiwan or in China to conduct a multipledose BE/BA study when the target product is modified release dosage form. » Accumulation index is easy – and actually the most interesting metric if we compare SD with MD. I only use » AUC_{0τ} (steady state)» R = ─────── » AUC_{0∞} (single dose)The formula is only for when conducting both a SD and a MD BE/BA studies simultaneously. If we just have a MD BE study, we still need a lambda_{z}. » V_{ss} is a strange metric. It sounds so easy to divide the Indeed. We calculate V_{ss} just because WinNonlin does so. Not a necessary procedure in a BE study. » That’s rubbish. WinNonlin uses » 1 » R = ────────────── » 1 – ℯ^{ –λz × τ} » which needs λ_{z}, a constant τ (what about a dose regimen of 6/6/12 or actual sampling times?), and is only valid for a onecompartmental model (the most serious drawback).[...] Good point! Since we're about to release next version (v2.3.3) of bear, we added data analysis for MD BE/BA since this release. I used to estimate lambda_{z} of MD study with the same method that we did in SD study. However, I was not very comfortable to do so for a long time. — All the best, Yungjin Lee bear v2.8.31: created by Hsinya Lee & Yungjin Lee Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear Download link (updated) > here 
Helmut Hero Vienna, Austria, 20090716 14:06 @ yjlee168 Posting: # 3959 Views: 8,062 

Dear Hsinya & Yungjin, » For what purpose to take blood sample after tau? Is it worth to do so? I only said that I have seen people doing so. IMHO, it does not make any sense. » » In steady state within τ you may get a value similar to SD, but with noisy data – and if more than one compartment is needed to describe [...] » So, it looks like that no lambda_{z}, no NCA... Why? According to my knowledge no guideline specific for MDstudies calls for λ_{z}. » » I would not try to play around with elimination from steady state within τ. An example for different λ_{z}estimates obtained from SD and MD for a twocompartment model (similar to this post, but τ=24h, 4 doses): Running WinNonlin’s PK model 11 (extravascular, first order absorption, 2 compartments, no lagtime, microconstants parametrization, w=1/y^{2}) we get
V1_F 76.41 L NCAestimation of λ_{z} from the last three points (12/14/24hr) gives 0.1233/hr (t½ 5.624hr) . If we use the predicted concentrations we would get 0.1030/hr (t½ 6.732hr) . Running a simulation of the dosage regimen and estimating λ_{z} from data in the last interval (84/86/96hr) we get 0.1397/hr (t½ 4.963) – which is faster than the SDestimate. Metaphorically speaking in logscale in any given dosage interval we place another ‘triangle’ on top of the remaining profile – it’s clear that the descending slope gets steeper. If one is really interested in λ_{z} and has no SDphase in the study, sampling should continue until concentrations from previous doses are washed out – I would expect any estimate within the MDprofile to be biased towards faster elimination.» It is inevitable for us in Taiwan or in China to conduct a multipledose BE/BA study when the target product is modified release dosage form. OK, same in the EU. » The formula is only for when conducting both a SD and a MD BE/BA studies simultaneously. If we just have a MD BE study, we still need a lambda_{z}. Do Chinese guidelines call for λ_{z}, accumulation index, ? » » V_{ss} is a strange metric. » Indeed. We calculate V_{ss} just because WinNonlin does so. That’s not a good reason. WinNonlin carries some really outdated legacy from previous versions. I talked to Simon last week, and it seems that Pharsight is reluctant in removing anything in order to keep backwardscompatibility. BTW, who needs an 80% confidence interval or – even worse – Westlake’s confidence intervals? Does anybody understand how WinNonlin calculates the ridiculous a posteriori power? » Since we're about to release next version (v2.3.3) of bear, we added data analysis for MD BE/BA since this release. Great! » I used to estimate lambda_{z} of MD study with the same method that we did in SD study. However, I was not very comfortable to do so for a long time. Given my comments from above I’m not convinced whether it is really needed and makes sense at all. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
yjlee168 Senior Kaohsiung, Taiwan, 20090716 22:17 (edited by yjlee168 on 20090716 22:34) @ Helmut Posting: # 3960 Views: 7,248 

Dear Helmut, » I only said that I have seen people doing so. IMHO it does not make any sense. I see. » » So, it looks like that no lambda_{z}, no NCA... » » Why? According to my knowledge no guideline specific for MDstudies calls for λ_{z}. Sorry about this. I was thinking something else. You're right. » » » I would not try to play around with elimination from steady state within τ. In Taiwan, we have to provide three C_{min}s before starting sampling for C_{ss(n)} at the steadystate (SS) for one dosing interval to prove that we do have C_{max(ss)} and AUC_{tau(ss)}. For example, if the tau is fixed at 24 hr, then we start dosing volunteers for 5 consecutive days. And on the 3^{rd}, 4^{th} and 5^{th} day, we need get each blood sample before next dose as C_{min}. So we will have 3 C_{min}s and a serial C_{(n)ss} within one tau at SS on the 6^{th} day as the attached plot. Unfortunately, sometimes these three C_{min}s data before SS can be quite noisy. It can be difficult to tell the SS has been reached. In this situation, we can provide halflife (T_{1/2}) at the same time to prove that the SS has been reached during the time period that we collect blood samples for one tau. For instance, If estimated T_{1/2} is 18 hr, then we do collect blood samples at SS since it has been 120 hr which is more than 5*T_{1/2} (90 hr). That's why we have to play with elimination from SS within tau. » [..] washed out  I would expect any estimate within the MDprofile to be biased towards faster elimination. Nice example. I did that once. I used nonlinear regression to fit conctime data obtained from a MD BE study. Of course, I tried 1, 2 and 3compartment PK models and then used AIC to pick the final model. From fitting results of the final model, I got T_{1/2} indirectly with further calculation. That helped me to explain "Hey! I really did sampling at SS." The approach was accepted with that case. » Do Chinese guidelines call for λ_{z}, accumulation index, ? No. Not even FDA, EMEA or Japan for MD BE study, as far as I remember. So no rule is the rule. » » » V_{ss} is a strange metric. » » Indeed. We calculate V_{ss} just because WinNonlin does so. » » That’s not a good reason. I know. Just because people or regulators have been getting used to WinNonlin. » WinNonlin carries some really outdated legacy from previous versions. I talked to Simon last week, and it seems at Pharsight is reluctant in removing anything in order to keep backwardscompatibility. BTW, who needs a 80% confidence interval or – even worse – Westlake's confidence intervals? Does anybody understand how WinNonlin calculates the ridiculous a posteriori power? , only can be heard exclusively at this Forum. » [...] added data analysis for MD BE/BA since this release. » » Great! We will still use ARS, TTT, or AIC or the combination methods as we do with SD BE study to estimate lambda_{z} without including C_{max}(ss) in bear. Options are up to user. » Given my comments from above I’m not convinced whether it is really needed and makes sense at all. explained as above. Many thanks. — All the best, Yungjin Lee bear v2.8.31: created by Hsinya Lee & Yungjin Lee Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear Download link (updated) > here 
oksanachlebko Junior Ukraine, 20180105 00:10 @ Helmut Posting: # 18146 Views: 1,909 

Dear Helmut! I kindly ask you to help me with the following question! » If I get an accumulation index in the MD study more or less different from 1 I try to give additional information, whether the drug shows true nonlinear PK, or only a small shift due to the second compartment. is it possible to distinguish true nonlinear PK and shift due to other compartments? What if the dose proportionality is proven but accumulation index is more than 1.4? All the Best! Oksana 