Mauricio Sampaio
★    

Brazil,
2015-10-07 02:24
(3095 d 18:04 ago)

Posting: # 15520
Views: 9,503
 

 Linear Pharmacokinetics of Levamlodipine [PK / PD]

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? :confused:

Best regads!
Mauricio Sampaio
★    

Brazil,
2016-06-04 00:33
(2854 d 19:55 ago)

@ Mauricio Sampaio
Posting: # 16393
Views: 7,599
 

 Linear Pharmacokinetics of Levamlodipine

❝ 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? :confused:


Hi members!
Somebody have any contribution with the question posted?
Mauricio Sampaio
★    

Brazil,
2016-06-06 18:19
(2852 d 02:09 ago)

@ Mauricio Sampaio
Posting: # 16402
Views: 7,550
 

 Quantification of S-amlodipine

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.
Helmut
★★★
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Vienna, Austria,
2016-06-06 22:23
(2851 d 22:05 ago)

@ Mauricio Sampaio
Posting: # 16403
Views: 7,452
 

 Quantification of S-amlodipine

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).

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nobody
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2016-06-07 10:29
(2851 d 09:59 ago)

@ Helmut
Posting: # 16404
Views: 7,369
 

 Quantification of S-amlodipine

❝ 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
Mauricio Sampaio
★    

Brazil,
2016-06-07 20:35
(2850 d 23:53 ago)

@ nobody
Posting: # 16407
Views: 7,397
 

 Quantification of S-amlodipine

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?
Helmut
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Vienna, Austria,
2016-06-08 03:32
(2850 d 16:56 ago)

@ Mauricio Sampaio
Posting: # 16412
Views: 7,274
 

 Quantification of S-amlodipine

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.

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Mauricio Sampaio
★    

Brazil,
2016-06-09 23:48
(2848 d 20:40 ago)

@ Helmut
Posting: # 16422
Views: 7,262
 

 Quantification of S-amlodipine

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!!!:-D

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!:cool:
martin
★★  

Austria,
2016-06-09 17:22
(2849 d 03:06 ago)

@ Mauricio Sampaio
Posting: # 16420
Views: 7,244
 

 Linear Pharmacokinetics of Levamlodipine

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
Mauricio Sampaio
★    

Brazil,
2016-06-10 00:03
(2848 d 20:25 ago)

@ martin
Posting: # 16423
Views: 7,278
 

 Linear Pharmacokinetics of Levamlodipine

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?
martin
★★  

Austria,
2016-06-12 23:48
(2845 d 20:40 ago)

@ Mauricio Sampaio
Posting: # 16428
Views: 7,348
 

 Linear Pharmacokinetics of Levamlodipine

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
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