Biomedical Engineering Reference
In-Depth Information
of TKI dosage is adapted to each patient according to individual plasma levels,
contributing to minimize the risk of major adverse reactions and to increase the
probability of efficient, long-lasting, therapeutic response. This chapter reviews the
bioanalytical developments by chromatography and mass spectrometry in the field
of targeted anticancer therapy, across the growing family of recent FDA-approved
oral TKIs as well as for tamoxifen and its active metabolites, being in fact the most
widely used targeted anticancer agent. The text also provides an introduction to
existing pharmacokinetics-pharmacodynamics knowledge in the field of targeted
anticancer therapy, and the rationale for a TDM program for TKIs.
1
Introduction
Cancer has become one of the most common diseases in developed countries. It is
the leading cause of death among men and women aged younger than 85 years in
the United States, above cardiovascular problems [
1
] . Fortunately, considerable
medical advances have been achieved in the field of cancer chemotherapy in the last
few decades, notably via the progressive optimization and improved management of
toxicities of approved anticancer drugs, or by the continuous discovery of novel
agents. Nowadays, treatment of many cancers relies on cytotoxic chemotherapy
regimens, sometimes in combination with radiation therapy and surgery. Standard
cytotoxic drugs used for cancer therapy have generally a narrow therapeutic index,
are nonspecific, as they target ubiquitous cell division mechanisms. In that context,
considerable research efforts have been pursued for finding specific treatments of
cancer [
2
], with limited success until 2000s, with the notable exception of all-trans
retinoic acid in Acute Promyelocytic Leukemia, and tamoxifen in breast cancer.
These two drugs, designed for binding to retinoic acid receptors (RAR) and
estrogen receptors (ER), respectively, can actually be considered the first clinically
used targeted anticancer agents that have been associated with high rates of treat-
ment success and control of the disease for prolonged period of time.
In the last decade, a new era of cancer therapy has emerged, and the treatment of
several cancers has shifted from cytotoxic and nonspecific chemotherapy to chronic
oral treatment with targeted molecular therapies. These treatments are characterized
by unique mechanisms of action and are highly specific for single or multiple key
cellular biological pathways responsible per se or implicated in the cancer process
[
3
]. Targeted therapy via protein kinase inhibitors is directed against (onco) proteins
allowing the modulation of various signaling pathways and is therefore character-
ized by more limited nonspecific toxicities. At present, 12 new oral targeted anti-
cancer agents have been approved by FDA (Table
1
), over 20 compounds are in
Phase I and II trials, and many more at various stages of preclinical development
[
3
]. Except for one agent (vemurafenib), all oral anticancer-targeted drugs approved
by FDA are tyrosine kinase inhibitors (TKIs), and will be collectively designated
thereafter as the generally accepted acronym TKIs.
