Optimization of therapy by pharmacokinetic-pharmacodynamic analyses

In cytotoxic anticancer agents, efficacy depends on tumor heterogeneity and is not evaluated immediately after administration, and toxicities are severe and life threatening such as neutropenia and thrombocytopenia. Therefore because toxicity is often more readily measured than efficacy, there are more reported pharmacodynamic (PD) studies defining relationships between pharmacokinetic (PK) parameters and the toxicity. However, retrospective studies have shown that molecular targeted agent systemic exposure correlates with treatment response (efficacy and toxicity) in various cancers including renal cell carcinoma (RCC). The evidence of the relationship between PK and PD for imatinib currently exists in the treatment of leukemia and gastrointestinal stromal tumor (GIST). It is important to evaluate the relationship between PK and PD prospectively in clinical trials rather than extrapolating from retrospective analyses. Based on these findings, therapeutic levels should be defined for molecular targeted agents in the treatment of RCC such as that that already occurs for antiepileptic, immunosuppressive, and antibiotic agents. Optimization of systemic exposure by dose modification to eliminate individual variability can increase the probability of efficacy, decrease the probability of toxicity, or both in each RCC patient treated with molecular targeted agents.