Alternative approaches for Phase I studies of anticancer drugs: a role for therapeutic drug monitoring.

The traditional approach to conducting Phase I studies of anticancer drugs is to select a starting dosage for humans based on preclinical data, then empirically escalate dosages in cohorts of patients until the maximum tolerated dosage (MTD) is established. Although this empirical study design has worked reasonably well and continues to be in widespread use, its statistical shortcomings and clinical inefficiencies have been recognized. An alternative strategy involves the use of pharmacokinetic principles to systematically escalate systemic exposure--area under the plasma concentration-time-curve (AUC)--instead of dosage of Phase I trials. Human trials are initiated at whatever patient-specific dosage is required to achieve an AUC equal to 1/10 the AUC in mice at the LD10 (or for children 80% of the AUC achieved in adults at the MTD), such that three patients at the first treatment level might receive three different dosages. If no dose-limiting toxicity is observed, the next cohort of patients receives whatever dosage is required to achieve the next higher AUC level, with AUC escalation continuing until the maximum tolerated systemic exposure (MTSE) is reached. By escalating systemic exposure instead of dosage, one adjusts for interpatient pharmacokinetic variability. This strategy will permit more precise dosage escalations and should more accurately establish the maximum level of treatment intensity for future Phase II trials.