Abstract
Efficacy of cancer pharmacotherapy depends upon drug exposure to the body and responsiveness of the tumor to the drug treatment. Drug exposure is determined by pharmacokinetics and dose, whereas responsiveness is intrinsically variable by tumor heterogeneity. Recently, a number of molecular targeting agents are used as promising therapy for cancers, and most of them are coupled with particular diagnostics which can predict treatment response. These diagnostics examine somatic mutations of individual cancers, and are used to distinguish responders and non-responders before choosing right patients and right drugs.On the other hand, lower drug exposure to the body also leads to insufficient efficacy. Although most of pharmacokinetic studies in the past were related to the toxicity of oncologic agents, a number of important evidences have been published recently on exposure-effect relationships for molecular targeting, chemotherapeutic and hormonal agents. For example, efficacy of tyrosine kinase inhibitor, imatinib in chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST) depended on plasma concentration of imatinib. Therefore, therapeutic drug monitoring (TDM) of imatinib has been introduced into clinical practice in Japan. Usefulness of TDM was also reported to improve the efficacy and safety of continuous 5-fluorouracil therapy. Individual variation in the capability of hepatic activation creates inter-individual variation in efficacy of the tamoxifen treatment. CYP2D6 is a key enzyme responsible for converting tamoxifen to active metabolites, endoxifen and 4-hydroxytamoxifen. The breast cancer patients who carry decreased-functional alleles of CYP2D6 showed lower plasma concentrations of endoxifen compared to patients with normal functional allele, probably resulting in worse clinical outcome in tamoxifen therapy. Knowledge of the exposure-response relationships becomes quite important for improving cancer pharmacotherapy.
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