RATIONAL DESIGN OF IRINOTECAN ADMINISTRATION BASED ON PRECLINICAL MODELS

Most clinical drug regimens for irinotecan (CPT-11 [Camptosar]) have b een empirically based on classic in vivo pharmacokinetic and pharmacod ynamic considerations, We propose an alternative approach Mat attempts to provide a rationally designed schedule of irinotecan administratio n based on preclinical data. HL60 cells grown in suspension or as subc utaneously implanted solid xenografts in nude mice served as in vitro and in vivo models to test the activity of irinotecan or its active me tabolite, SN-38. For SN-38, within an effective drag concentration ran ge, scheduling drug administration based on duration of DNA synthesis inhibition significantly potentiated cell kill in vitro, and increasin g drug concentrations at suboptimal scheduling did not result in addit ive cell kill. These data suggested Mat even though high drug doses ma y be attainable in vivo, they may riot be required to achieve maximum antitumor activity. To test Mis hypothesis, a sensitive in vivo model to test Me toxicity and antitumor activity of CPT-11 is required, whic h is provided in the human myeloid HL60 xenograft model grown in nude mice. In this model, CPT-11 at a dose 50 mg/kg, daily x 5 (MTD) achiev ed 100% complete tumor regression. This model should be useful to test the hypothesis that for irinotecan, administration of a minimum effec tive dose (MED) at an optimal schedule carl achieve Maximum antitumor activity and should therefore prevail over Me classic approach of admi nistering the MTD.