Preclinical and Clinical Development of Exatecan (DX-951f)

The principal rationale for synthesizing exatecan (DX-8951f, Daiichi Pharmaceutical Co., Ltd, Japan) was to exploit physicochemical features of the camptothecins (CPTs) anticipated to yield an increased therapeutic advantage compared with currently available CPT analogs such as topotecan and irinotecan. The overall therapeutic profile sought in these efforts was greater and broader antitumor activity, decreased toxicity, and intrinsic activity without requiring metabolic activation, which may accentuate the fundamentally large interindividual variability in the pharmacologic behavior of the CPT analogs and consequently in their antitumor and toxicologic profiles. Exatecan has completed Phase I clinical development on a broad range of schedules and is currently undergoing more focused disease-directed Phase II and Phase III evaluations. Additionally, DE-310, a unique polymer prodrug of exatecan, which was developed to achieve protracted systemic exposure to the active drug after a single dose, is also undergoing early clinical development.