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Mauricio Sampaio ★ Brazil, 2015-10-07 02:24 (3449 d 15:05 ago) Posting: # 15520 Views: 10,691 |
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Dear, anybody have references about linear pharmacokinetics of Levamlodipine between 2,5 - 5,0 mg? Levamlodipine is also known as levoamlodipine or S-amlodipine and it is a pharmacologically active enantiomer of amlodipine. Can I conclude if amlodipine (racemic mixture) has linear pharmacokinetics, levamlodipine follows the same behavior?  Best regads! |
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Mauricio Sampaio ★ Brazil, 2016-06-04 00:33 (3208 d 16:56 ago) @ Mauricio Sampaio Posting: # 16393 Views: 8,580 |
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❝ anybody have references about linear pharmacokinetics of Levamlodipine between 2,5 - 5,0 mg? ❝ ❝ Levamlodipine is also known as levoamlodipine or S-amlodipine and it is a pharmacologically active enantiomer of amlodipine. Can I conclude if amlodipine (racemic mixture) has linear pharmacokinetics, levamlodipine follows the same behavior? Hi members! Somebody have any contribution with the question posted? |
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Mauricio Sampaio ★ Brazil, 2016-06-06 18:19 (3205 d 23:10 ago) @ Mauricio Sampaio Posting: # 16402 Views: 8,529 |
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Dear, Amlodipine is a racemic mixture of [-]S and [+]R-enantiomeric forms, with the S-amlodipine, also known as Levamlodipine, having analgesic activity. Considering the main objective in bioanalysis will be development an achiral method, simple, sensitive, rapid and reliable mass spectrometry for the quantification of S-amlodipine in human plasma. I ask you,...can I use Amlodipine (racemic) instead of S-amlodipine (enantiomeric form) as analitical standard? Note: The volunteers just will administrate Levamlodipine. |
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Helmut ★★★   Vienna, Austria, 2016-06-06 22:23 (3205 d 19:06 ago) @ Mauricio Sampaio Posting: # 16403 Views: 8,430 |
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Dear Mauricio, we have done that for other drugs where only the racemate is commercially available as a certified standard. You have to assess and quantify the enantiomeric purity (which is not given in the CoA). Had no issues with the EMA (current GL). — 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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nobody nothing 2016-06-07 10:29 (3205 d 07:00 ago) @ Helmut Posting: # 16404 Views: 8,335 |
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❝ You have to assess and quantify the enantiomeric purity (which is not given in the CoA). Hy! in my strange parallel-universe I would have to have at least one pure enantiomer to do this, or am I totally wrong with this? — Kindest regards, nobody |
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Mauricio Sampaio ★ Brazil, 2016-06-07 20:35 (3204 d 20:53 ago) @ nobody Posting: # 16407 Views: 8,360 |
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I agree with you Nobody. If the analytical response of S-amlodipine present in racemic compound is the same of isolate enantiomer using chiral method, I can determinate the purity. But, in my case, I do not have a chiral method available in bio-analysis. Then, I keep my doubt...can I use Amlodipine (racemic) instead of S-amlodipine (enantiomeric form) as analitical standard? Both standard are available on the market, but I can not aquire the pure enantiomere in short time. What are the guaranties of my correct quantification of S-Amlodipine in plasma with a method that do not make any difference between R and S enantiomeres present in analitical reference standard? |
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Helmut ★★★ Vienna, Austria, 2016-06-08 03:32 (3204 d 13:57 ago) @ Mauricio Sampaio Posting: # 16412 Views: 8,263 |
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Hi Mauricio, I incorrectly assumed that you have a chiral method. Sorry. ❝ What are the guaranties of my correct quantification of S-Amlodipine in plasma with a method that do not make any difference between R and S enantiomeres present in analitical reference standard? There are none. In our case the enantiomeric ratio of the 'racemate' was in fact not 1:1 (checked by MS-MS response and circulardichroism after heart-cut of the eluted peaks). Do you have the study samples already in the fridge without a validated method method? If yes (bad) I would immediately order the certified l-enantiomer. Validate the method with the racemate but state in the protocol that you will correct all concentrations once you have the l-enantiomer. Analyze the study samples with the racemate standards / QCs. This is a last resort - better than to wait for the enantiomer standard and risk that the samples degrade in the meantime. Avoid it in the future. — 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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Mauricio Sampaio ★ Brazil, 2016-06-09 23:48 (3202 d 17:41 ago) @ Helmut Posting: # 16422 Views: 8,245 |
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Hi Helmut and all members who contributed. ❝ I incorrectly assumed that you have a chiral method. Sorry. No problem my friend! ❝ Validate the method with the racemate but state in the protocol that you will correct all concentrations once you have the l-enantiomer. Analyze the study samples with the racemate standards / QCs. This is a last resort - better than to wait for the enantiomer standard and risk that the samples degrade in the meantime. Avoid it in the future. There is still time!!!  Thank you so much! Now I understood that calibrators prepared and quality control samples concentration will not be accurate. Because weighing of standard is a racemate! So, concentration of unknown samples will be inaccurate.  S-Amlodipine, let's go!  |
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martin ★★ Austria, 2016-06-09 17:22 (3203 d 00:06 ago) @ Mauricio Sampaio Posting: # 16420 Views: 8,219 |
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Dear all, Please note that there is hardly no way to show or proof linear PK in clinical studies. You usually assess dose-proportionality which is a consequence of linear PK (i.e. linear PK implies dose-proportionality but not necessarily vice versa). best regards & hope this helps Martin |
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Mauricio Sampaio ★ Brazil, 2016-06-10 00:03 (3202 d 17:26 ago) @ martin Posting: # 16423 Views: 8,258 |
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Dear Martin ❝ Please note that there is hardly no way to show or proof linear PK in clinical studies. You told.."In clinical studies!" Question: is there any other way to proof linear PK or your text mean...PK linear is a theoric concept? like linear coefficient (r2) = 0,9999999 ❝ You usually assess dose-proportionality which is a consequence of linear PK (i.e. linear PK implies dose-proportionality but not necessarily vice versa). How many is accepted dose-proportional? 5%, 10%, 15% between diferent strengths? |
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martin ★★ Austria, 2016-06-12 23:48 (3199 d 17:40 ago) @ Mauricio Sampaio Posting: # 16428 Views: 8,330 |
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Dear Maurico, Here is some more background regarding linear PK you may find useful: Linear kinetics: All transport processes follow a first order kinetic Transport processes: absorption, distribution and/or elimination First order kinetic: The concentration is changed at a rate proportional to the concentration Non-linear kinetic: One or more transport process(es) follow other than first order kinetic, for example: Zero order kinetic: The concentration is changed at a constant rate Michaelis-Menten kinetic: The change of concentration over time is a function of the drug concentration (capacity limited processes) On assumption of linear kinetics PK parameters AUC and Cmax increase proportional with dose PK parameters tmax , t1/2, CLs, Vss, MRT and F are independent of dose Dose-proportionality studies allows assessing dose-related changes in exposure but not necessarily time related changes (e.g. auto induction of metabolizing enzymes, inhibitor formation, etc). Regarding acceptance criteria you may find the following paper of interest: Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welsch PA, Callaghan JT and Forgue ST (2000). Confidence interval criteria for assessment of dose proportionality. Pharmaceutical Research, 17(10):1278-1283. hope this helps & best regards martin |
Ing. Helmut Schütz