Pharmacological considerations in high-dose chemotherapy.

Recent advances in pharmacokinetic/pharmacodynamic analysis have been applied to the development of anticancer agents. In addition, there has been an increase in the interest in pharmacokinetic/pharmacodynamic analysis in relation to the field of high-dose (HD) chemotherapy. The basis for investigation of the concept of the dose-response relationship in HD should be the "exposure-response relationship", this can be investigated in phase I and pharmacology trials of HD chemotherapy designed to define the relationship between escalation of the target drug dose and exposure. Whether pharmacokinetics are linear or nonlinear is important in the determination of optimal dosing. Nonhematological toxicities have become more important than hematological toxicities as pharmacodynamic parameters in HD chemotherapy; however, the relationship between drug exposure and the clinical outcome remains unclear. Cellular concentration and plasma exposure are important predictors of clinical effect. Wide interpatient pharmacokinetic or exposure variability is more important in HD chemotherapy than in conventional-dose chemotherapy due to the increase in the frequency and severity of nonhematological toxicities. Drug-drug interactions are also important issues in HD chemotherapy, although definitive evidence is difficult to obtain. Future investigations of HD chemotherapy are warranted on the basis of pharmacokinetic/pharmacodynamic analysis.