Tyrosine kinase inhibitors becoming generic drugs - risks and chances from a regulatory perspective

Abstract

Aim: To provide a systematic overview on: i) safety profiles; ii) pharmacokinetic parameters; and iii) regulatory framework of anti-cancer tyrosine kinase inhibitors (TKI). Methodology: Recherché of pharmakokinetic (PK)-parameter: i) Germany's federal drug database (public domain part) was accessed in November 2013. Section 5.2 (PK) of Summary of Product Characteristics systematically was searched for available PK-parameters, and ii) A search in PubMed/Medline was performed also in November 2013 using the international non-proprietary name of the respective medicinal product combined with the term 'early phase' or 'dose escalation'. PubMed recherché was restricted by searching only in clinical trials. Safety profile assessment: On 11 November 2013, Summary of Product Characteristics of currently marketed medicinal products was accessed. Side effects were categorized as mentioned in the table's legend by frequency for each preferred term of the systems organ class system. Source: Summary of Product Characteristics published on the Heads of Medicines Agencies homepage: http://mri.medagencies.org/Human Results: PK-parameters and safety profiles are presented in the respective tables. Throughout the text, clinical meaning, orphan drug status and current discussion on narrow therapeutic index (NTID)-status by European committees and working parties is discussed. Conclusion: Tyrosine kinase inhibitors are a valuable addition of the therapeutic armamentarium. Especially in certain haematologic diseases, i.e. chronic myeloid leukaemia (CML)-therapy, TKI have revolutionized pharmacotherapy with survival rates not significantly different from healthy matched population. However, as their safety profile differs substantially from conventional cytostatic drugs, new side effects impact on patient's quality of life. About ten years after first substances were authorized, patent protection will end within the next years. Thus, product specific guidance is needed to accurately perform bioequivalence studies and file marketing authorization applications for registration of TKI-generics.