Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective

Abstract

Over the last decades, billions have been spent and huge efforts have been taken in basic and clinical cancer research [CA Cancer J Clin 63: 11-30]. About a decade ago, the arms race between drugs and cancer cells reached a new level by introduction of tyrosine kinase inhibitors (TKI) into pharmacological anti-cancer therapy. According to their molecular mechanism of action, TKI in contrast to so-called “classic” or “conventional” cytostatics belong to the group of targeted cancer medicines, characterized by accurately fitting with biological structures (i.e. active centers of kinases). Numerous (partly orphan) indications are covered by this new class of substances. Approximately ten years after the first substances of this class of medicines were authorized, patent protection will end within the next years. The following article covers clinical meaning and regulatory status of anti-cancer TKI and gives an outlook to what is expected from the introduction of generic anti-cancer TKI.

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

“…Two major groups of molecularly targeted drugs are currently in clinical use for cancer therapy. One group includes potent inhibitors of a variety of signaling molecules that are essential for the proliferation of tumor cells, such as inhibitors of various tyrosine kinases as well as of the Raf‐MEK and PI3K‐mTOR (mammalian target of rapamycin) signaling pathways . The other group consists of mAbs to surface molecules that are highly expressed in particular cancers, such as rituximab (to CD20 in lymphoma), trastuzumab (to HER2 in breast cancer), and cetuximab (to epidermal growth factor receptor [EGFR] in colon cancer).…”

“…One group includes potent inhibitors of a variety of signaling molecules that are essential for the proliferation of tumor cells, such as inhibitors of various tyrosine kinases as well as of the Raf-MEK and PI3K-mTOR (mammalian target of rapamycin) signaling pathways. [33][34][35][36][37] The other group consists of mAbs to surface molecules that are highly expressed in particular cancers, such as rituximab (to CD20 in lymphoma), trastuzumab (to HER2 in breast cancer), and cetuximab (to epidermal growth factor receptor [EGFR] in colon cancer). These mAbs are thought to bind to their targets on tumor cells and thereby induce the killing of these cells by complement-dependent cytotoxicity as well as via ADCP mediated by macrophages and ADCC mediated by NK cells, both of which require the interaction of Fc receptors on the effector cells with the Fc domain of the bound mAbs.…”

Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition

“…These enzymes can phosphorylate many regulatory proteins in the cell and can activate signal transduction cascades, triggering many cellular functions involving cell growth and proliferation. Many TKIs have been developed to date, including imatinib, nilotinib, and dasatinib (inhibit BCR-ABL), gefitinib and erlotinib (inhibit epidermal growth factor receptor (EGFR)), vandetanib (inhibits vascular endothelial growth factor receptor (VEGR), EGFR, and rearranged during transfection (RET)), sunitinib (inhibits fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGFR), axitinib and pazopanib (inhibit VEGFR, c-KIT, and PDGFR), tandutinib (inhibits FLT3, PDGFR beta, and c-Kit), sorafenib (inhibits VEGFR, PDGFR, and Raf ), crizotinib (inhibits anaplastic lymphoma kinase (ALK)), vemurafenib and dabrafenib (inhibit BRAF), trametinib (inhibits MEK1/2), and many others (Eckstein et al, 2014;Eigentler, Meier, & Garbe, 2013;Hartmann, Haap, Kopp, & Lipp, 2009;Jackson & Chester, 2014;Levitzki, 2013;Wiernik, 2010). The inhibited target proteins of these TKIs can also be found in Table 2.…”

Tirosyne Kinase Inhibithors (TKIs) in the Treatment of Non –Small Cell Lung Cancer (NSCLC), Practical Pharmacological Aspects

“…The major metabolites of Dasatinib are 4 (BMS-582691), M5 (BMS-606181), M6 (BMS-573188), for erlotinib is NorErlotinib (OSI-420) and for Gefitinib NorGefitinib (M523595). 12 Oral absorption of EGFR TKIs is slow to moderate and has significant variability both within the same individual and from one individual to another. Plasma concentrations of gefitinib are obtained 3-7 hours after administration to healthy subjects and patients with solid tumors.…”