Critérios para determinação de bioequivalência de medicamentos de índice terapêutico estreito

Abstract

Since 1999, the National generic policy has brought great benefit to the population because of increased competition and hence, decreased average price of drugs. Considering the entire legal framework of non-innovator drugs set out in the guidelines of international regulatory agencies and the fragility of narrow therapeutic index drugs regarding their potential for ineffectiveness or adverse events, it’s of the utmost importance that Brazil revise the guidelines on the requirements for registration of generic and similar drugs of this category. Thus, the general objective of this work was to propose the limits alteration of relative bioavailability / bioequivalence studies of these drugs, following the limits already established by other regulatory agencies. To do this, a survey of the criteria adopted by the FDA, EMA, NIHS (Japan), Health Canada and WHO was carried out, and it was also evaluated which drugs are considered of narrow therapeutic index. As a result of this study, it was proposed narrowing the limits of bioequivalence of drugs with narrow therapeutic index to 90.00 to 111.11%. The drugs valproic acid, carbamazepine, cyclosporine, digoxin, phenytoin, lithium, sirolimus, tacrolimus, theophylline and warfarin were chosen as a narrow therapeutic index drug. After analyzing the scaled bioequivalence technique followed by the FDA, it was decided not to use this model. It was proposed to change the mandatory limits for the AUC parameter of the chosen drugs, and change the limits for Cmax for the drugs cyclosporine, digoxin, phenytoin and lithium carbonate. It was suggested that these changes be included in the revision of the legislation dealing with the relative bioavailability / bioequivalence tests.