The studies reviewed herein support the precept that "systemic dose-intensity" (i.e., systemic exposure) may be more informative than "administered dose-intensity" for certain anticancer drugs. This does not mean that the administered dose-intensity should be ignored; in fact these data indicate the importance of documenting and assessing administered dose-intensity as an initial step toward identifying those situations where systemic dose-intensity may be most important. The studies described in this review were selected as representative examples of successful clinical pharmacodynamic studies; other published examples include
vincristine AUC versus severity of neurotoxicity,
etoposide systemic exposure versus
leukopenia, red cell concentration of
mercaptopurine metabolites versus
neutropenia in children with ALL, and
ARA-CTP retention in leukemic blasts versus clinical response in acute non-
lymphocytic leukemia. As is the case with other types of clinical trials in
cancer patients, there are also examples of negative pharmacodynamic studies (i.e., no relationship found between concentration and effects). There are several possible reasons for such negative findings, including the lack of such a relationship for some drugs, measuring the inappropriate
drug moiety (e.g., failure to measure all active metabolites), measuring
drug concentrations in the wrong
biological fluid, evaluating systemic exposure over too narrow a range (i.e., all patients have either sub- or supra-therapeutic systemic exposure), selecting inappropriate sampling times or pharmacokinetic parameters, inadequately assessing
drug toxicity or response, or simply studying an inadequate number of patients or patients with
drug-resistant
cancers. Therefore, negative findings in some pharmacodynamic studies should not deter the investigation of other drugs and/or other malignant diseases, just as negative therapeutic trials do not preclude subsequent clinical trials in oncology. Also, finding a relation between systemic exposure and
drug toxicity, in the absence of a clear relation to antitumor effects, is potentially of great clinical utility. Such data should allow more objective escalation of
drug dosages in individual patients, to ensure maximum dose-intensity while avoiding host toxicity. Obviously, if such dose escalation could be guided by more easily measured patient characteristics (e.g., age, weight, CrCl, shoe size, etc.), then using
drug concentrations in individual patients might be obviated.(ABSTRACT TRUNCATED AT 400 WORDS)