IDAMYCIN® (idarubicin hydrochloride) for injection is a new antileukemic anthracycline analogue, which differs from its parent compound, daunorubicin, by the absence of a methoxy group at position 4 (Fig 1). This absence confers appreciable increases in lipophilicity and DNA binding ability.[l2, l3] The nomenclature and chemical properties of IDAMYCIN are summarized in IDAMYCIN is formulated as a sterile powder in 5 mg and 10 mg single-use only vials. Each vial contains 5 mg or 10 mg of idarubicin hydrochloride and 50 mg or 100 mg of Lactose N.F. as an orange-red, Iyophilized powder. Stability studies have demonstrated that idarubicin HCI active drug substance may be stored for up to 3 years at room temperature (15° to 30°C) in amber glass bottles.
Mechanism Of Action
The mode of action of IDAMYCIN is not qualitatively different from its parent, daunorubicin. Fluorescence studies of drug affinity for daunorubicin have shown that, in cell-free systems, IDAMYCIN has an affinity, similar number of DNA binding sites, and inhibitory effect on topoisomerase, an intracellular enzyme considered target for this class of drugs; activity comparable to daunorubicin. As suggested by Neidle, the absence of noncoplanarity of the C-4 methoxycarbonate atom in IDAMYCIN, with respect to rings A, B, and C of the aglycone moiety, may in effect result in a deeper penetration within the DNA helix into the intercalation site(s). In fact, in intact tumor cells, IDAMYCIN has been shown by Capranico et al to induce a higher number of double- and single-strand DNA breaks ISSB) than those observed with daunorubicin or doxorubicin. Higher penetration, greater intercalation reported for IDAMYCIN, relative to daunorubicin and doxorubicin, is apparently consistent with its high partition coefficient, and tendency for extensive intracellular tissue uptake and distribution, all resulting from the removal of the 4-methoxy group of daunorubicin.
In Vitro Pharmacologic Activity
When compared with daunorubicin and doxorubicin against a number of leukemia and solid tumor cell lines, IDAMYCIN was observed to have the following increases in potency: against leukemia cell lines, 13- to 18-fold; against ovarian carcinoma, about 11-fold; against HeLa cells, 2- to 150-fold; and against human colon cell lines. 5- to 15-fold
*Relative potency = ID50(DOX)/ID50 (IDA or DNR); ID50 = dose inhibiting 50% of cell growth or colony formation. µResults are from three separate experiments. Using the tumor stem cell assay, IDAMYCIN® also demonstrated greater cytotoxic activity than daunorubicin and doxorubicin against a battery of freshly established human adenocarcinomas. When inhibiting the cloning efficiency of exponential phase HeLa cells, IDAMYCIN was 27 to 100 times more active than daunorubicin. (See Table 3.) In fact, IDAMYCIN has shown significantly higher activity against cell lines resistant to daunorubicin, like LoVo/Dox and P388/Dox, indicating incomplete cross-resistance between IDAMYCIN and doxorubicin. In experimental leukemias, its antileukemic activity was five to eight times more potent than daunorubicin and four to ten times more potent than doxorubicin (potency in relation to optimal antitumor dose).[21,22]
IDAMYCIN® has demonstrated extensive activity against a variety of murine leukemias and Iymphomas commonly used for evaluation of anticancer effects. Table 4 shows the effect of IDAMYCIN compared to daunorubicin and doxorubicin against ascitic P388, L1210 leukemias, and EL-4 Iymphoma.[21, 23]
Following IP treatment at optimal doses, IDAMYCIN exhibited a comparable antileukemic effect as, and was approximately five to six times more potent than, doxorubicin, or the parent compound, daunorubicin, in the P388 and L1210 systems. Greater activity with IDAMYCIN has also been seen aher treatment of early or late IV injected L1210 leukemia. This is of particular interest since L1210 leukemia is known to have partial natural resistance to anthracyclines.
In the EL-4 lymphoma model, IDAMYCIN demonstrated a better therapeutic effect than daunorubicin with a similar potency difference. Optimal responses were found when IDAMYCIN was used IV to treat disseminated (IV transplanted) murine L1210 and Gross leukemias. Table 5 shows that IDAMYCIN significantly prolonged survival time of mice bearing advanced L1210, whereas daunorubicin was inactive even at 10-fold higher doses. Using the Gross leukemia model, IDAMYCIN was shown to be 5 to 10 times more potent than daunorubicin with equal or greater antileukemic activity.
*Dose which caused 20% or less toxic deaths. ¶Median survival time of treated animals/median survival time of controls x 100. ∂Value reported as mean survival time.
Antineoplastic activity of IDAMYCIN has been tested against several solid murine tumors. In all models tested, IDAMYCIN IV was active at 4- to 10-fold lower doses than daunorubicin or doxorubicin.
IDAMYCIN was as effective as daunorubicin on sarcoma 180 and less effective than doxorubicin against early mammary carcinoma of mice.
IDAMYCIN&174; was active only at toxic doses against advanced mammary carcinoma and MSV induced tumors.
IDAMYCIN showed spectrum of activity similar to that of doxorubicin against a number of human solid tumors (breast, lung, melanomo, ovarian, sarcoma) xenogralied into nude mice.
When given orally, IDAMYCIN has been found to be as active as doxorubicin, and more active than daunorubicin, on IV inoculated L1210 leukemia.
In pharmacologic studies designed to compare relative adverse activity on the heart, 25 IDAMYCIN® was found considerably less cardiotoxic than either daunorubicin or doxorubicin at optimal therapeutic doses in the Bertozzoli mouse model. (See Table 6 ) IDAMYCIN was also found less adverse than doxorubicin on the cardiovascular system of rats
In general, IDAMYCIN was observed to produce equal or lesser adverse effects than doxorubicin on the immune system of mice.
At the lowest IV dose tested, IDAMYCIN delayed gastric emptying in rats without interfering with basal biliary secretion
Skin ulcerations, which developed around the site of intradermal in jection of IDAMYCIN, were comparable in size, appearance, duration, and time of peak expression to those induced by equivalent amounts of doxorubicin and daunorubicin in mice, rats, and swine. [10,27]
IDAMYCIN was observed to have no adverse effect on the central nervous system even at doses higher than the LD50. And in a series of in vitro and in vivo studies, no effect was noted on the auto nomic nervous system.