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jag009 ★★★ NJ, 2012-03-15 20:05 (4797 d 14:11 ago) Posting: # 8280 Views: 7,917 |
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Hi, Would someone give me some idea on the following case? It sounds a bit simple but what is the proper way to determine Kel from the elimination phase, based on noncompartmental analysis, if the last measurable timepoint has a higher concentration than the adjacent timepoint? Should Kel be labelled as "Undefined"? Some CROs would say "Undefined" but there are others who would determine Kel as long as the linear regression result based on the timepoints involved (at least 3) is acceptable. Thanks Edit: Category changed. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2012-03-16 02:46 (4797 d 07:29 ago) @ jag009 Posting: # 8281 Views: 6,991 |
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Dear Jag! ❝ […] what is the proper way to determine Kel from the elimination phase, based on noncompartmental analysis, if the last measurable timepoint has a higher concentration than the adjacent timepoint? Proper? Two pharmacokineticists = ≥3 methods.  ❝ Should Kel be labelled as "Undefined"? Some CROs would say "Undefined" … That would mean excluding the subject’s AUCs (AUCt unreliable, AUC∞ undefined). At least you could keep the subject’s Cmax in the data set (which is more variable). ❝ … but there are others who would determine Kel as long as the linear regression result based on the timepoints involved (at least 3) is acceptable. Others = most, IMHO. As long as you are consistent, perform the estimation of λz blinded for treatment, and have an SOP in place it shouldn’t be problematic.* PK software by default mark excluded datapoints both in the plots and tabulated output. A moderately higher last value is not that uncommon, especially if the last sampling interval is relatively short compared to the half-life. Just think about acceptable analytical (in)accuracy and (im)precision: 15% within the calibration range and 20% at the LLOQ. Example: t½ 8 h, last two sampling points (interval = t½) theoret. ±inacc/±imprec. obs.Even if the method is performing within specs, two values with deviations of opposite direction already lead to equal concentrations. A little bit more random noise and voilà!
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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jag009 ★★★ NJ, 2012-03-26 17:24 (4786 d 17:52 ago) @ Helmut Posting: # 8335 Views: 6,504 |
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Hi Helmut, ❝ ❝ Should Kel be labelled as "Undefined"? Some CROs would say "Undefined" … ❝ ❝ That would mean excluding the subject’s AUCs (AUCt unreliable, AUC∞ undefined). At least you could keep the subject’s Cmax in the data set (which is more variable). Actually that particular CRO (maybe there are others) kept the subject's Cmax, Tmax and AUCt but assigned AUCinf, kel and t1/2 as undefined or "N.C." One more question, what if the last two points of the elimination phase is going in the positive direction and the points before them (lets say 3 points, yes after Cmax) are declining? |
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Helmut ★★★ Vienna, Austria, 2012-03-28 16:30 (4784 d 18:46 ago) @ jag009 Posting: # 8338 Views: 6,548 |
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Dear John! ❝ ❝ That would mean excluding the subject’s AUCs (AUCt unreliable, AUC∞ undefined). At least you could keep the subject’s Cmax in the data set (which is more variable). ❝ ❝ Actually that particular CRO (maybe there are others) kept the subject's Cmax, Tmax and AUCt but assigned AUCinf, kel and t1/2 as undefined or "N.C." That doesn’t make sense from a (European) regulatory perspective, IMHO. For EMA the primary metric for extent of absorption is AUCt, but you have to demonstrate that it’s a reliable estimate: AUCt/AUC∞ ≥0.8. For IR products this does not make sense, since absorption is expected to be already complete after 2–4×tmax. After this cut-off point estimates are stable, only variability increases (see papers by Endrényi, Midha, Tóthfalusi). Interesting enough FDA (where both AUCt and AUC∞ are primary metrics) no clear statement is made about AUCt. We find only: […] we recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more terminal half lives of the drug. […] The sample collection can be spaced in such a way that the […] terminal elimination rate constant (λz) can be estimated accurately. At least three to four samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. It seems that AUCt can be kept in the analysis.❝ One more question, what if the last two points of the elimination phase is going in the positive direction and the points before them (lets say 3 points, yes after Cmax) are declining? Good question, next question. For the FDA I would trigger reanalysis (pharmacokinetic repeat) – SOP in place, no cherry-picking (blinded for treatment), justification in the report which value was used in the final analysis.— 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 |
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ElMaestro ★★★ Denmark, 2012-03-29 20:57 (4783 d 14:18 ago) @ jag009 Posting: # 8348 Views: 6,540 |
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Hello Jag, ❝ One more question, what if the last two points of the elimination phase is going in the positive direction and the points before them (lets say 3 points, yes after Cmax) are declining? This happens actually quite frequently in inhalation and nasal BE studies. It really, really stinks and is PP implausible when the last value is 3x the previous one and the preceding 6 values have been dropping nicely etc. Plausibility (or foul smell for that matter) is, however, not always a good reason to ignore anything. Therefore more meat to the bone is necessary. When I see it I usually tell my clients to have a look at the bioanalytical validation and possibly consider an audit. Silly clients will flat out refuse auditing* while wiser clients will do it. Once the dust settles things sometimes make more sense. Best regards, EM. * typical excuses:
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Ing. Helmut Schütz