Bioequivalence and Bioavailability Forum

Dear TOT!

❝ […] we keep getting statements like this from authorities: A multiple dose study at the highest dose strength is considered to be most sensitive model for detecting differences.

Very interesting. In some particular cases valid (see below).

❝ Can someone explain why that would be so? And are there papers that discuss this?

Some basic work was done by the FDA^1,2 and recently by a Spanish group.^3,4 Note one of the co-authors.

From the last papers’ concluding remarks:

Parent drug in single dose is usually the most sensitive analyte for demonstration of bioequi­va­lence in case of drugs with linear kinetics and only hepatic pre-systemic metabolism. The only exception to this general rule is BCS Class III drugs with low intrinsic clearance, which are ex­pected to be very infrequent and to show non-linear kinetics due to limited absorption caused by a limited operative absorption time or absorption window. In this exceptional case the parent drug in steady state seems to be the most sensitive analyte.³
It can be concluded that when the pre-systemic metabolism (linear or non-linear) of the parent drug is only hepatic, metabolite does not show higher sensitivity than parent drug to changes in the pharmaceutical performance. The outcome of this simulation work supports the present requirement of a steady state design in case of dose- (or time-) dependent pharmacokinetics in addition to single dose investigation detailed in the CHMP Note for Guidance on the Investi­ga­tion of Bioavailability and Bioequivalence since, in the investigated pharmacokinetic model with saturated hepatic first-pass metabolism of the parent drug, the steady state design has shown to be more sensitive to detect differences between formulations in some of the investigated scenarios. It would be the responsibility of the applicant to investigate (e.g. with the metho­do­logy described in this simulation work) the pharmacokinetic model of the drug under investi­ga­tion to identify whether the additional steady state study is necessary and should be required or not.⁴

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1. Chen M-L and AJ Jackson
   The Role of Metabolites in Bioequivalence Assessment. I. Linear Pharmacokinetics without First-Pass Effect
   Pharm Res 8(1), 25–32 (1991)
   
2. Chen M-L and AJ Jackson
   The Role of Metabolites in Bioequivalence Assessment. II. Drugs with Linear Pharmacokinetics and First-Pass Effect
   Pharm Res 12(5), 700–8 (1995)
   
3. Fernández-Teruel C, Nalda Molina R, González-Alvarez I, Navarro-Fontestada C, García-Arieta A, Casabóa VC, and M Bermejo
   Computer simulations of bioequivalence trials: Selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Linear kinetics (I)
   Eur J Pharm Sci 36, 137–46 (2009)
   
4. Fernández-Teruel C, González-Alvarez I, Navarro-Fontestada C, García-Arieta A, Bermejo M, and VG Casabó
   Computer simulations of bioequivalence trials: Selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Part II. Non-linear kinetics
   Eur J Pharm Sci 36, 147–56 (2009)