Pharma_88 ☆ India, 2020-08-27 18:07 (1560 d 09:28 ago) Posting: # 21893 Views: 8,464 |
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Dear All, We are thinking to perform steady state BE study for XXX submission where Test product is ER formulation and Reference product is IR formulation. Further, Its HVD product. So, question is whether is this feasible to conduct replicate BE IR vs ER and if yes then what are the parameters for conclusion? Thanks. — Regards, Pharma_88 |
Helmut ★★★ Vienna, Austria, 2020-08-27 19:32 (1560 d 08:02 ago) @ Pharma_88 Posting: # 21894 Views: 7,666 |
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Hi Pharma_88, ❝ We are thinking to perform steady state BE study for XXX submission… Unfortunately my crystal ball is in the laundry and reading tea leaves turned out to be an insufficient substitute. Hence, which XXX? ❝ … where Test product is ER formulation and Reference product is IR formulation. <nitpick> Not BE, but comparative BA. You can only hope for similar extent of absorption but never for rate of absorption in a comparison of ER vs IR. Furthermore, BE means similarity in PK metrics of interest if equimolar doses are administered. Sometimes one has to increase the ER dose to get similar AUCs… Whatever is applicable in your case, BE is the wrong term. </nitpick> ❝ Further, Its HVD product. So, question is whether is this feasible to conduct replicate BE IR vs ER and if yes… Is it a highly variable drug 1 or are one – or both – products 2 highly variable? But, in principle, yes. ❝ … then what are the parameters for conclusion? Once you tell us what XXX is, we can possibly help.
— 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 |
Pharma_88 ☆ India, 2020-08-31 12:26 (1556 d 15:09 ago) @ Helmut Posting: # 21898 Views: 7,575 |
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❝ ❝ We are thinking to perform steady state BE study for XXX submission… ❝ ❝ Hence, which XXX? Its for EMEA. ❝ ❝ … where Test product is ER formulation and Reference product is IR formulation. ❝ ❝ Not BE, but comparative BA. You can only hope for similar extent of absorption but never for rate of absorption in a comparison of ER vs IR. Furthermore, BE means similarity in PK metrics of interest if equimolar doses are administered. Sometimes one has to increase the ER dose to get similar AUCs… Whatever is applicable in your case, BE is the wrong term. </nitpick> Can you please elaborate to understand. If you can provide me any supportive literature to go in detail its really helps me. ❝ ❝ Further, Its HVD product. So, question is whether is this feasible to conduct replicate BE IR vs ER and if yes… ❝ ❝ Is it a highly variable drug or are one – or both – products highly variable? But, in principle, yes. ❝ ❝ ❝ … then what are the parameters for conclusion? ❝ ❝ Once you tell us what XXX is, we can possibly help. EMEA — Regards, Pharma_88 |
Helmut ★★★ Vienna, Austria, 2020-08-31 14:21 (1556 d 13:13 ago) @ Pharma_88 Posting: # 21901 Views: 7,776 |
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Hi Pharma_88! ❝ Its for EMEA. The EMEA (European Agency for the Evaluation of Medicinal Products) was renamed to EMA (European Medicines Agency) fifteen years ago. ❝ ❝ Not BE, but comparative BA. You can only hope for similar extent of absorption but never for rate of absorption in a comparison of ER vs IR. Furthermore, BE means similarity in PK metrics of interest if equimolar doses are administered. Sometimes one has to increase the ER dose to get similar AUCs… Whatever is applicable in your case, BE is the wrong term. </nitpick> ❝ ❝ Can you please elaborate to understand. If you can provide me any supportive literature to go in detail its really helps me. Very nitpicking: Even if release characteristics of products are identical (say, IR vs IR, MR vs MR) there are no “BE studies”. Bioequivalence is the desired outcome of a comparative BA study. One assessor of Poland regularly did not accept study protocols which mentioned BE in the title. His response was essentially: “If you already know the outcome, why do you want to perform a study at all?” But to reiterate: Bioequivalence means similar rate and extent of absorption after equimolar doses. The PK metrics for rate are generally Cmax and for extent AUC0–t. For modified release products AUC0–∞ is required as well (contrary to the FDA where all three are always required). Depending on the product characteristics additional PK metrics are required. 1When comparing MR to IR, the rate of absorption might be similar (i.e., for delayed release products, where only tmax will be different) or different (i.e., for prolonged / controlled / extended / sustained release products). In the latter case, this is a desired property:
❝ ❝ ❝ … then what are the parameters for conclusion? See the applicable MR guideline, Section 5. Note that if you want to compare a new MR product to an established IR product, this is not a generic application acc. to Directive 2001/83/EC, Article 10(2)(b) but a hybrid application. For the required PK studies 3 see Section 5.1 and for the therapeutic studies Section 5.2 (only if you are extremely lucky, they might be waived). For the required PK metrics see Section 6.8.2. In case of high variability, reference-scaling according to the EMA’s ABEL (Average Bioequivalence with Expanding Limits) is acceptable for the following PK metrics:
For details about ABEL see the IR-GL Section 4.1.10 and the Q&A document Section 8. Note that in order to plan for ABEL, you have to give a sound justification that expanding the common BE limits is clinically not relevant (contrary to RSABE for the U.S. FDA and China’s CDE/NMPA; don’t forget this step). I recommend a full replicate design (4 periods TRTR|RTRT or 3 periods TRT|RTR 6) and not the partial replicate design (TRR|RTR|RRT). For the pros and cons see this post.
Additionally between-subject variability of the MR product should be compared with that of the IR product by a one-sided test (non-superiority). PowerTOST .— 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 |
Pharma_88 ☆ India, 2020-09-08 11:05 (1548 d 16:30 ago) @ Helmut Posting: # 21910 Views: 7,441 |
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Thanks For your detailed response. I have a few questions and need your suggestion in this regards. I have kept following parameters in SS study (IR VS ER). Primary pharmacokinetic parameters: AUC0-τ,ss Secondary pharmacokinetic parameters: Day 01 to 04-Morning dose: Cpd Day 04 (Morning dose): Cτ,ss, Cmax,ss, Cmin,ss, Tmax,ss, accumulation index, %Fluctuation and Cav Please correct me. and also want to know for Cpd and Cτ,ss: Cpd: All pre-dose samples needs to be considered including profiling day sample or only samples before profiling day? Cτ,ss: How to calculate it? Whether morning dose of Day 04 is also need to be taken in to account to calculate. Thanks. — Regards, Pharma_88 |
Helmut ★★★ Vienna, Austria, 2020-09-08 19:25 (1548 d 08:10 ago) @ Pharma_88 Posting: # 21911 Views: 7,606 |
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Hi Pharma_88, ❝ I have kept following parameters in SS study (IR VS ER). PK metrics, pleeze. ❝ Primary pharmacokinetic parameters: AUC0-τ,ss OK. ❝ Secondary pharmacokinetic parameters: ❝ Day 01 to 04-Morning dose: Cpd OK. No comparison – just report them. ❝ Day 04 (Morning dose): Cτ,ss, Cmax,ss, Cmin,ss, Tmax,ss, accumulation index, %Fluctuation and Cav ❝ ❝ Please correct me. If you don’t have a lag-time, Cmin,ss (the ‘true’ minimum concentration) should be very similar to both Cpd and Cτ,ss. Cmin,ss is required only for originators. Since a hybrid application is closer to a generic, you could drop it. AFAIK, the accumulation index \(\frac{1}{1-\exp (-\lambda_\textrm{z}\cdot \tau)}\) is not required by any agency. You would need a reliable estimate of \(\small{\lambda_\textrm{z}}\), which you may not obtain for the ER formulation in all subjects. As long as you don’t have flip-flop PK (see below), \(\small{\lambda_\textrm{z}}\) is a property of the drug and therefore, not relevant for comparing products. Cav is not informative because it is simply AUC0–τ/τ. If you want you can report it though without a statistical comparison. The outcome will be exactly the same as for AUC0–τ. Cav is only needed for the calculation of fluctuation. ❝ Cpd: All pre-dose samples needs to be considered including profiling day sample or only samples before profiling day? You have to collect at least three pre-dose samples in order to demonstrate achievement of steady-state. In your case mornings of days 2–4. See also this presentation (slide 14). ❝ Cτ,ss: How to calculate it? Whether morning dose of Day 04 is also need to be taken in to account to calculate. Nope. It’s the concentration at the end of the (last) dosing interval or in your case at 96 hours. Too lazy to search but the EMA states somewhere that this sample should be collected with a time deviation of ≤10 minutes. In my studies I always used the estimated concentration at τ. Let’s explore three examples. One-compartment model, no lag-time, D 100, V 5, t½,el 14 h, t½,abs 1 h (IR). Pseudo-steady-state reached after 5 × 14 = 70 h, results for the profile day 4.
Since you mentioned before that you have to deal with a HVD(P), you can expand the limits for some PK metrics (see this post) if the study will be performed in a replicate design. You don’t need a treatment-free washout, i.e., the built-up of a subsequent steady states can overlap with the washout from the previous one. Example for a full replicate design, where T = ER and R = IR. Profile days in red.
— 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 |