Bioequivalence and Bioavailability Forum

Dear Ohlbe!

❝ … what if the drug which is still detected induces or inhibits the metabolism of the drug which is no longer detected ?

That’s a very good point!
One of the prerequisites of a crossover design is that subjects in later period(s) are in the same physiological state than in the drug-naïve first. This is not necessarily always the case – even after a ‘suitable’ washout. Examples:

• A multiple dose study of the auto-inducer car­bama­ze­pine is more sensitive to detect differences between formations than a single dose study (esp. of the rate of BA).^1,2
  
• In crossover studies of biosimilars unequal carryover was regularly observed in the past, unavoidable biasing the treatment effect. There­fore, studies should be performed in a parallel design.^3,4

Assessing pre-dose concentrations in a crossover design is only one piece of the cake. As usual: Know the PK of the drug and your formulation. If no data of DDIs of the components of the FDC are available, a small pilot study would help.

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1. Tóthfalusi L, Endrényi L. Approvable generic carbamazepine formulations may not be bioequivalent in target patient populations. Int J Clin Pharmacol Ther. 2013; 51(6): 525–8. doi:10.5414/cp201845.
   
2. Schütz H. Steady-state studies. Presentation at: Network of Scientific Excellence. Campinas, BR. 11–13 February, 2020. Online.
   
3. EMA, CHMP. Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins. London. 24 January 2007. Online.
   
4. Schütz H. Unequal carry-over – “solved” in BE but still an Issue in Assessing Biosimilarity? Satellite Short Course at the 2^nd Annual Biosimilars Forum. Budapest. 5 October 2017. Online.