Bioequivalence and Bioavailability Forum

Hi David,

❝ There isn't any biological background that might explain this issue? Or problems during manufacturing?

No idea.

❝ This is really awkward... the CI and point estimate are far more "perfect" than I am used to see.

For this drug, not. The relative BA (against a solution) is ~100% and the variability low to moderate. Check out the NDAs and ANDAs at FDA’s site. You will find a lot of studies with similarly narrow CIs (even with much smaller sample sizes).

❝ In fact, in full replicate studies, I've seen reference drugs "performing" poorly when compared with single administrations of themselves...

Normal for HVD(P)s.

❝ Is the dose-toxicity so sensible for this drug that event the narrower limits does not apply in this case?

No idea.

❝ Did a quick search and haven't find any study reporting the dose-response of this drug

The FDA’s guidance gives this explanation:

FDA has concluded that levothyroxine sodium is a narrow therapeutic index (NTI) drug 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.