Bioequivalence and Bioavailability Forum

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

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 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.

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.