drcampos
★    

Brazil,
2007-04-24 06:46
(6183 d 19:56 ago)

Posting: # 689
Views: 8,955
 

 Levothyroxine formulations [Design Issues]

Dear All,

I would like to evaluate the disposition of lower dosages of levothyroxine formulations, i.e 12,5 mg and 37.5 mg (new formulations). Considering the FDA Guidance it is necessary a dose of 600 mcg for avoinding baseline effect. So, the problem is the dose (48 tablets x 12.5 mcg = 600 mcg). Does someone have experience with these studies?

Regards,

Daniel
drcampos
★    

Brazil,
2007-07-19 23:56
(6097 d 02:47 ago)

@ drcampos
Posting: # 913
Views: 7,685
 

 Levothyroxine BE

Dear All,

Could someone provide information (articles) about linear pharmacokinetics of strenghts of levothyroxine sodium (25, 50, 75, 88, 100, 112, 125, 137, 150, 200 and 300 ug).

I intend to develop a BE study with the highest strength and ask for biowaiver to the lowest strenghts, because a dose of 600ug (2x 300ug) should be given to detect T4 above baseline levels according FDA Guidance (Levothyroxine Sodium Tablets — In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing - 2000).

Regards,

Daniel Rossi de Campos
Brazil

--
Edit: moved to previous thread. [HS]
pjs
★    

India,
2015-07-29 13:32
(3165 d 13:11 ago)

@ drcampos
Posting: # 15166
Views: 6,246
 

 Levothyroxine BE

Dear all,

We are preparing three strengths of the Levothyroxin sodium oral solution 25 mcg/5ml, 50 mcg/5ml and 100 mcg/5ml for EMA submission.

Any one could provide some reference for the pharmacokinetic linearity of the same.

Also is levothyroxine considered as a NTI?

RMS is UK.

Thanks.
Regards,
PJS
Helmut
★★★
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Homepage
Vienna, Austria,
2015-07-29 14:43
(3165 d 12:00 ago)

@ pjs
Posting: # 15167
Views: 6,734
 

 BE of a solution, NTID or not…

Hi PJS,

❝ We are preparing three strengths of the Levothyroxin sodium oral solution 25 mcg/5ml, 50 mcg/5ml and 100 mcg/5ml for EMA submission.


Hhm, see the BE-GL, Section “Oral solutions”:

If the test product is an aqueous oral solution at time of administration and contains an active sub­stance in the same concentration as an approved oral solution, bioequivalence studies may be waived. However if the excipients may affect gastrointestinal transit (e.g. sorbitol, mannitol, etc.), absorption (e.g. surfactants or excipients that may affect transport proteins), in vivo so­lubility (e.g. co-solvents) or in vivo stability of the active substance, a bioequivalence study should be conducted, unless the differences in the amounts of these excipients can be ad­e­­quately justified by reference to other data. The same requirements for similarity in excipients apply for oral solutions as for Biowaivers.


❝ Also is levothyroxine considered as a NTI?

❝ RMS is UK.


The jury is still out.

The FDA concluded that levothyroxine is a NTID based on the following evidence:
  • The range between serum levothyroxine the­ra­peu­tic and toxic concentrations is narrow;
  • Some levothyroxine-associated toxicities are serious and/or irreversible;
  • Sub-therapeutic levothyroxine concentrations result in inadequate treatment and lead to poor clinical outcomes;
  • Levothyroxine sodium requires individual dose titration to achieve a satisfactory balance between maximizing efficacy and minimizing serious dose-related toxicity;
  • Therapeutic drug monitoring based on serum TSH and total or free-T4 levels is routinely employed to facilitate levothyroxine dose titration; and
  • Levothyroxine has small-to-medium within-subject variability.
… and recommended reference-scaling in Dec 2014.

See MHRA’s Jan 2013 review, Section “Is levothyroxine a Narrow Therapeutic Index Drug?”:

Levothyroxine has been referred to as a drug with a narrow therapeutic index (NTI) in several published articles although this is debatable.
The therapeutic index (also known as therapeutic ratio), is a comparison of the amount of a the­ra­peutic agent that causes the therapeutic effect with the amount that causes adverse re­actions. Drugs with narrow therapeutic index are drugs with small differences between the­ra­peu­tic and toxic doses. There is no agreed European definition but the U.S. FDA provides the fol­low­ing definition for a NTI drug:

  1. There is less than a 2-fold difference between the minimum toxic and minimum effective con­cen­tra­tions in the blood, and
  2. Safe and effective use of the drug products requires careful titration and patient monitoring.

Acute toxicity and a possible need for therapeutic dose monitoring are usually key characteristics of NTI drugs in practice. However a weekly dose of thyroxine (usually a multiple of the patient’s daily dose) has been administered in clinical practice under direct observation, when there are con­cerns over possible compliance issues; this dosage regimen appears to be well tolerated.
The FDA guidance on bioequivalence studies in levothyroxine advises that a single dose of 600 mcg is administered to healthy volunteers and this dose also appears to be generally well tolerated.
Therefore, acute toxicity with well over double the daily requirement of levothyroxine does not seem to pose safety risks, at least over the short term. In this sense, levothyroxine does not fall into the NTI category.
It has been shown that small changes in serum levothyroxine and liothyronine concentrations, within the normal range, alter serum TSH, indicating a sensitive negative feedback relationship between serum free levothyroxine and TSH. It is possible that in some patients once the optimal dose of levothyroxine has been achieved, they could suffer loss of control of their thyroid dis­ease as a result of any subsequent variability in the amount of levothyroxine administered.
Therefore although levothyroxine does not meet the criteria for being a narrow therapeutic index drug, there are strong indications that small changes in the delivered dose of levothyroxine, should they persist over long term treatment, could have significant clinical consequences.


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pjs
★    

India,
2015-07-29 15:05
(3165 d 11:37 ago)

@ Helmut
Posting: # 15168
Views: 6,132
 

 BE of a solution, NTID or not…

Dear helmut,

Thanks for the reply.

Regards,
PJS
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