Bioequivalence and Bioavailability Forum

Hi Libaiyi,

steady state studies were proposed for Highly Variable Drugs / Drug Products in the 1990s.^1–4 Consequently, they were also recommended in a European Note for Guidance.⁵ However, this recommendation was removed in the final version⁶ because single dose studies are more sen­sitive in detecting potential differences in formulations (especially of the rate of absorption C_max / t_max).

It is notable that none of the extant guidelines offer steady state studies as a viable alternative to single dose for HVD(P)s. Consider reference-scaling instead.

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1. Midha KK, Blume HH, editors. Bio-International. Bioavailability, Bio­equi­va­lence and Pharmacokinetics. Stutt­gart: med­pharm; 1993. ISBN 3-88763-019-X.
   
2. Blume HH, Midha KK. Bio-International 92, Conference on Bioavailability, Bio­equi­va­lence, and Pharmacokinetic Studies. J Pharm Sci. 1993; 82(11): 1186–9. doi:10.1002/jps.2600821125.
   
3. Blume H, Zhong D, Elze M, Wendt G, Schug B, Scheidel B, Hutt HJ, Hagenlocher M. Advantages of a steady-state crossover design in assessment of bioequivalence of highly variable drugs: propafenone. Europ J Pharmaceut Sci. 1994; 385–93. doi:10.1016/0928-0987(94)00068-9.
   
4. Blume HH, Midha KK, editors. Bio-International 2. Bioavailability, Bioequivalence and Pharmacokinetic Studies. Stutt­gart: med­pharm; 1995. ISBN 3-88763-040-8.
   
5. EMEA Human Medicines Evaluation Unit / CPMP. Note for Guidance on the In­ves­tigation of Bioavailability and Bio­equi­va­lence. Draft. London. 17 December 1998.
   
6. EMEA, CPMP. Note for Guidance on the Investigation of Bioavailability and Bio­equi­va­lence. London. 26 July 2001. Online.