Title

 

Authors

C. Blandizzi
 
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa

 

Abstract

Generic medicinal products are ‘copies’ of patented drugs, which can be marketed at low cost following patent expiration of the respective ‘branded’ drugs. As a consequence of increasing restrictions in the economic resources allocated to public health programs, most governments support the use of generic drugs, and their regulatory authorities have issued guidelines illustrating the conditions under which these products can be recognized as interchangeable (i.e., therapeutically equivalent) to their branded counterparts.For drugs intended to exert systemic therapeutic actions, the documentation of interchangeability is usually based on the principles of bioequivalence, and it requires comparative pharmacokinetic evaluations, which are carried out as single-dose, cross-over studies in healthy volunteers. However, pharmacokinetic bioequivalence testing is not a suitable way for documenting interchangeability of generic copies of locally acting branded drugs, which are assumed to exert their therapeutic effects at the site of administration, and for which a systemic action, if any, would be regarded as an undesired effect [1]. Examples of locally acting medicinal products include orally administered antibiotics, such as rifaximin, which are devoid of significant systemic absorption and are intended to exert their antibacterial action within the gut lumen. Due to their peculiar physicochemical properties, these antibiotics are virtually not absorbed by the gastrointestinal mucosa, thereby achieving high faecal concentrations, with good efficacy against various enteric infections, while minimizing the risk of both systemic antimicrobial resistance and adverse effects [2]. When developing generic products of locally acting antibiotics as oral formulations, it must be considered that changing the physicochemical properties of the active ingredient or changing the non-active ingredients may significantly influence the pharmacokinetics, and thereby the efficacy and/or safety profiles, of the generic product, which, as such, can not be considered as therapeutically interchangeable with the originator branded product [1]. For example, at the solid state rifaximin can be either amorphous or crystalline (five polymorphic forms, designated as α , β , γ , δ  and ε ), and its branded formulation contains only the polymorph α . The amorphous form and the other polymorphs of rifaximin are known to differ significantly from polymorph α  in terms of physicochemical properties and systemic bioavailability, following oral administration [3]. As a consequence, clinical data available for the brand product can not be translated to novel formulations of rifaximin containing other polymorphs, for which the characteristic of poorly absorbable locally acting antibiotic must be proven by adequate pharmacological investigations. In general, according to current guidelines, efficacy clinical trials are required to demonstrate therapeutic equivalence between generic and branded products containing locally acting antibiotics. However, in some instances, human pharmacodynamic or local availability studies can be sufficient, provided that the proposed studies and methodology are adequately justified. In addition, safety issues have to be addressed appropriately [1].
 
[1] European Agency for the Evaluation of Medicinal Products (1995) Clinical requirements for locally applied, locally acting products, containing known constituents. CPMP/EWP/239/95. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003687.pdf
[2] C. Scarpignato, I. Pelosini (2005) Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 51 (Suppl 1), 36-66.
[3] G.C. Viscomi et al. (2008) Crystalforms of rifaximin and their effect on pharmaceutical properties. CrystEngComm 10, 1074-1081.