Bioequivalence and Bioavailability Forum

Dear all,

bioequivalence is not science (i.e., challenging a falsifiable hypothesis through experiments) but rather an ad hoc solution to a pressing problem in the 1970s. Its two main assumptions were plucked out of thin air:

• A 20% difference in rate and extent of absorption is considered clinically not relevant and
  
• similar plasma concentrations in healthy subjects can be extrapolated to the patient population (i.e., similar therapeutic effects / AEs are expected).

Though not science in the strict sense, empiric evidence shows that the concept “works”:

• The few case reports telling the opposite might also be explained by non-compliance or the nocebo effect.
  
• Originators trying to dispute the concept (i.e., performing therapeutic equivalence studies in patients v.s. BE) failed: If TE passed, BE passed as well and vice versa.
  
• In short: “There are no dead people lying in the streets.” (© Helmut Schütz)

Did we just discover the first black swan?
Following concern by the French ANSM in 2012 about stability issues Merck KGaA changed one of the excipients of their levothyroxine sodium formulation Levothyrox, namely lactose to mannitol and citric acid. BE was demonstrated in a 2×2×2 crossover study in healthy subjects¹ (204 completers) with pre-specified limits of 90.00–111.11% for AUC and C_max according to the EMA’s GL (NTID). Both the new and old formulations were administered as a single 600 µg dose (3×200 µg). PK-metrics were adjusted for the baseline.
PE of AUC_0–72 was 99.3% (90% CI: 95.6–103.2%) and of C_max 101.7% (98.8–104.6%), both easily fulfilling the requirements for BE. Post-hoc power was >99%.

However, within three months of the new formulation’s release to the French market, AEs skyrocketed (dizziness, cramps, headaches, and hair loss). Within 24 days the ANSM received 9,000 (!) AE-reports. The French Minister of Health adressed these patients concerns on September 15^th by asking Merck to reintroduce the previous formulation within 15 days, on a temporary basis and under medical prescription only for patients with persistent and undesirable side effect.^2,3 An analysis of 5,062 patient complaints by the ANSM concluded that while ‘thyroid imbalances can occur for some patients during the transition’ between the old and new formulations, the reported symptoms ‘are in line with those experienced with the previous formulation. No new type of adverse event related to the new formulation was found’.⁴

Now what?

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1. Gottwald-Hostalek U, Uhl W, Wolna P, Kahaly GJ. New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin. 2017;33(2):169–74. doi:10.1080/03007995.2016.1246434.
   
2. Macdonald G. French police visit Merck KGaA Lyon plant as part of levothyrox probe.
   in-Pharma Technologist. 05-Oct 2017. online.
   
3. Melville NA. Side Effects Skyrocket in France With Levothyroxine Reformulation. Medscape. October 11, 2017. online.
   
4. ANSM. Point d’actualité sur le Levothyrox et les autres médicaments à base de lévothyroxine – Communiqué. 11/10/2017. online.