Narrow therapeutic index drugs: bioequivalence and generics

作者：Le Corre Pascal^*

来源：Presse Medicale, 2010, 39(2): 169-176.

DOI：10.1016/j.lpm.2009.09.017

The market share of generic drugs in France is quite low compared to that in other European countries. Because the scientific aspects of bioequivalence that govern the use of generics are sometimes described ambiguously in the literature, they ore not always perceived clearly by health professionals. This lock of clarity may be on obstacle to their use.
Two drugs are considered bioequivalent if the upper and lower limits of the 90% confidence interval (90% Cl) of the generic-to-brand ratio for the area under the curve (AUC) and for the maximum plasma concentration (Cmax) are included in the [-20%, +25%] interval. This interval applies to the 90% Cl of the ratios of the AUC (or Cmax) and not directly to the ratio of their values. Hence, it is wrong to consider that there is a -20% to + 25% variation in the AUC (and thus in the bioavailability) between a generic and G brand-name drug. This mistake con sometimes be seen in the medical literature, however, with incorrect extrapolations.
The bioequivalence is defined for a generic in relation to a brand-name drug. Consequently, two different generics of the some proprietary drug do not automatically meet the criteria for bioequivalence. Their interchangeability con present problems, especially for drugs with a narrow therapeutic Index, that is, those that have a < 2-fold difference between the minimum toxic concentration rind minimum effective concentration in blood.
More restrictive criteria have been proposed for narrow therapeutic index drugs, but there is currently no international consensus on the subject. Determining individual bioequivalence would require modified study protocols to guarantly the interchangeability of the brand-name and generic drugs so that a patient taking one formulation could change to another that would provide the same efficacy God safety
Some antiepileptic drugs have biopharmaceutical and pharmacokinetic properties inducing high levels of intraindividual variability, which can cause problems. According to the French drug agency (AFSSAPS), however, a link between epileptic attacks and treatment with generic drugs has not been established.
The economic evaluation of generics should go beyond the simple comparison of the soles price, especially for drugs with a narrow therapeutic range for which therapeutic drug monitoring (plasma assays) can be used.

• 出版日期2010-2