Idarubicin (4-demethoxydaunorubicin). A preliminary overview of preclinical and clinical studies.

4-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is superior to that of daunorubicin (DNR) or doxorubicin (DX). The drug is more potent than DNR and DX and is active by both the intravenous and the oral routes of administration. After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug. Idarubicinol has been shown to be an active metabolite in experimental models, being as potent and as active as the parent compound. Phase II clinical trials of Idarubicin have indicated that: By I.V. route Idarubicin is a potent antileukemic agent active in relapsed or refractory, ANLL, ALL (adult and pediatric) either as single agent or in combination with Ara-C at doses of 8-12 mg/m2 by i.v. day 1, 2 and 3 or 7-8 mg/m2 i.v. daily X 5 days (adults). There is evidence of lack of cross-resistance with parent drugs and other antileukemic agents. Phase III studies in previously untreated acute leukemias have been initiated. By oral route Idarubicin has antitumor activity in breast cancer at the doses of 35-45 mg/m2 q 3-4 weeks or 15 mg/m2 daily X 3 days q 3-4 weeks. Idarubicin has activity as a single agent in adult leukemias at the doses of 20-30 mg/m2/day X 3 days. The safety of administration (no risk of extravasation), the good tolerability and the reduced potential for cardiac toxicity, make oral Idarubicin particular attractive for further clinical development. Whether Idarubicin proves to be more effective and/or less cardiotoxic in clinical therapy than DNR or DX remains to be seen through prospective randomized studies which have been already initiated both in leukemias and solid tumors.