Abstract

Note for Guidance on the Investigation of Bioavailability and Bioequivalence,
CPMP/EWP/QWP/1401/98, EMEA, 26 July 2001, presents general rules for
generic drugs registration. For majority of generally acting drugs - simple
single-dose, 2-period, 2-sequence, crossover bioequivalence study in young
healthy volunteers in fasting state is usually performed. The decision regarding bioequivalence is based on 90% confidence intervals for AUC and Cmax ratios (test/reference) being within 80-125% for log-transformed data. For many years, such approach was criticized as inappropriate for some drugs with narrow therapeutic range, also called as "critical dose drugs". As a result of scientific debate, a new EMEA Guideline on the Investigation of Bioequivalence is coming into operation in 2009. The class of narrow therapeutic index drugs (NTDIs) is formally created for agents with steep concentration response relationship for efficacy and/or toxicity. These drugs require dosage individualisation based on therapeutic drug monitoring or titrated according to clinical response as a high risk of serious clinical consequences is expected in the event of too low or too high concentrations. All primary immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus, and everolimus) can be easily and undoubtedly considered as NTDIs. However, the classification as NTDI must be made individually for particular drug. In these specific cases, the acceptance interval for AUC and Cmax ratios may need to be tightened to 90-111%. Moreover, in individual cases additional or alternative requirements might be set. Described standards oblige Registration Agencies to obey more restrictive rules for generic products of immunosuppressive drugs.

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