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Idamycin

PRECLINICAL PHARMACOLOGY

Table of Contents

Description

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).[10] This absence confers appreciable increases in lipophilicity[11] 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.[10]

26H27NO9 ∑ HCI
TABLE 1: NOMENCLATURE AND CHEMICAL PROPERTIES OF IDAMYCIN® [10]
GENERIC NAME (idarubicin hydrochloride) for injection IDAMYCIN®
TRADE NAME IDAMYCIN®
CHEMICAL NAMES lyxo-hexopyranosyl) oxy]-7, 8, 9, 10-tetrahydro-6, 9, 11-trihydroxyhydrochloride, (7S-cis)-; (7S,9)--9-acetyl-7, 8, 9,10-tetrahydro-6,7, 9,11-tetrahydroxy-7-0-(2',3',6'-trideoxy-3'- amino-alpha-L-lyxohexopyranosyl)-5, 12-naphthacenedione hydrochloride
OTHER NAMES 4-Demethoxydaunorubicin
(4-dmDNR) (4-DMDR) (4DDM) NSC 256439
MOLECULAR FORMULA
MOLECULAR WEIGHT
PHYSICAL CHARACTERISTICS
APPEARANCE Orange-red, lyophilized powder
MELTING POINT 173°-174°C (with decomposition)
SOLUBILITY Soluble in sodium chloride and dextrose. Slightly soluble in water. Sparingly soluble in methanol. Practically insoluble in nonpolar organic solvents
POLYMORPHISM No polymorphic forms, ruled out by differential scanning calorimetric (DSC) analysis
pKa VALUE idarubicin HCl in water is 8.5.
pH 5 mg/mL solution of idarubicin in water is 5.0 to 6.5.
COMPATIBILITY Structurally related to daunorubicin and other napthacenequinones.
Physically incompatible with heparin; prolonged contact with alkaline solutions will result in degradation.

Please see Section 7 for additional compatibility information.

Figure 1: Structural Formulas of Idamycin® and Daunorubicin

Idamycin and Daunorubin

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,[14] similar number of DNA binding sites,[11] and inhibitory effect on topoisomerase[11], an intracellular enzyme considered target for this class of drugs; activity[15] comparable to daunorubicin. As suggested by Neidle,[16] 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[17] 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,[18] 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[19]

TABLE 2: CYTOTOXIC EFFECT OF IDAMYCIN AND DAUNORUBICIN ON VARIOUS CELL LINES EXPRESSED RELATIVE TO THE POTENCY OF DOXORUBICIN*[10]
COMPOUND P388 MURINE LEUKEMIA CEM HUMAN LEUKEMIA NIL 8 HAMSTER OVARIAN HeLa HUMAN CERVICALµ LoVo HUMAN COLON CoLo 205 HUMAN COLON
Doxorubicin 11 1 1 1 1
IDAMYCIN 18 13 11 143
1.9
3.1
4.8 15
Daunorubin
4.7 1.4 2
0.9
1
1.41.5

*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.[19] When inhibiting the cloning efficiency of exponential phase HeLa cells, IDAMYCIN was 27 to 100 times more active than daunorubicin.[20] (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]

TABLE 3: COLONY-FORMING ABILITY OF CULTURED HeLa CELLS IN EXPONENTIAL GROWTH, AFTER TREATMENT WITH DAUNORUBICIN, IDAMYCIN, AND DAUNORUBICIN DERIVATIVES[20]

HeLa cells in exponential growth (2 days aher seeding) were treated with graded concentrations of the tested compounds. After 2, 8, or 24 hr of exposure to the drugs, cells were washed, trypsinized, and plated (200 cells/plate; 3 replicates/group). Colonies were counted on the sixth day.

The median inhibitory dose was determined from dose-effect lines. The data represent the means of at least two separate experiments.


CONCENTRATION (nm) REQUIRED FOR 50% INHIBITION AFTER EXPOSURE FOR:
COMPOUND 2 HR 8 HR 24 HR
Daunorubicin 55.2 ± 8.2* 54.0 ± 13.0 21.2 ± 3.54
IDAMYCIN 1.7 ± 0.03 2.0 ± 0 0.3 ± 0.06
IDAMYCIN (Beta anomer) 26.0 ± 2.0 22.0 ± 2.0 13.2 ± 0.15
4-Demethoxy-7,9-di-epi-daunorubicin >200>200 >200
4-Demethoxy-7,9-di-epi-daunorubicin (Beta anomer) >200 >200 >200
*Mean ± S.E.

In Vivo Pharmacologic Activity

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.[21]

In the EL-4 lymphoma model, IDAMYCIN demonstrated a better therapeutic effect than daunorubicin with a similar potency difference.[23] 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.[21]

TABLE 4: ACTIVITY OF IDAMYCIN IN COMPARISON TO DAUNORUBICIN AND DOXORUBICIN AGAINST ASCITIC MURINE LEUKEMIA AND LYMPHOMA[21,23]
TUMOR
SYSTEM
TREATMENT
SCHEDULE

COMPOUND
OPTIMAL DOSE*
(mg/kg)
T/C
(%)
P388
(ascitic)
IP Day 1 IDAMYCIN
daunorubicin
0.8
4.0
188
197
L1219
(ascitic)
IP Day IDAMYCIN
daunorubicin
doxorubicin
0.7
4.0
10.0
156
156
205
EL-4
(ascitic)
IV Day 1 IDAMYCIN
daunorubicin
3.2
18.0
222
155
IV Day 3 IDAMYCIN
daunorubicin
doxorubicin
3.0
15.0
10.0
193
121
171

*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.[10]

IDAMYCIN was as effective as daunorubicin on sarcoma 180 and less effective than doxorubicin against early mammary carcinoma of mice.[10]

IDAMYCIN&174; was active only at toxic doses against advanced mammary carcinoma and MSV induced tumors.[10]

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.[24]

When given orally, IDAMYCIN has been found to be as active as doxorubicin, and more active than daunorubicin, on IV inoculated L1210 leukemia.[21]

TABLE 5: COMPARATIVE ACTIVITY OF IDAMYCIN AND DAUNORUBICIN AGAINST DISSEMINATED MURINE LEUKEMIAS[10,21]

TUMOR SYSTEM TREATMENT
SCHEDULES
COMPOUNDOPTIMAL DOSE*
(mg/kg)
T/C
(%)
L1210 IV,
Day 3,7,11
IDAMYCIN
daunorubicin
1.13
11.20
150
114
GROSS
LEUKEMIA
IV,
Day 1
IDAMYCIN
daunorubicin
3.30
16.90
233
167
IV,
Day 1,2,3
IDAMYCIN
daunorubicin
0.75
6.00
185
185
IV,
Day 1-5
IDAMYCIN
daunorubicin
0.50
4.00
196
186
IV,
Day 1,3,6
IDAMYCIN
daunorubicin
1.13
7.50
250
166
IV,
Day 1,4,7
IDAMYCIN
daunorubicin
0.75
7.50
215
153
IV,
Day 1,5,9
IDAMYCIN
daunorubicin
1.13
7.50
364
130
IV,
Day 3,6,9
IDAMYCIN
daunorubicin
1.13
9.30
166
150

*Dose which caused 20% or less toxic deaths. Median survival time of treated animals/median survival time of controls x 100.

Safety Pharmacology

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[18]

In general, IDAMYCIN was observed to produce equal or lesser adverse effects than doxorubicin on the immune system of mice.[26]

At the lowest IV dose tested, IDAMYCIN delayed gastric emptying in rats without interfering with basal biliary secretion[10]

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.[10]

TABLE 6: CARDIOTOXICITY OF IV IDAMYCIN IN THE BERTAZZOLI MOUSE MODEL[10,28]
SPECIES
(STRAIN)
SEX
SCHEDULE OF
TREATMENT
TIME
BETWEEN
1ST INJECTION
& NECROPSY

SINGLE
DOSES
(mg/kg)

CUMULATIVE
DOSE
(mg/kg)
MINIMAL
CUMULATIVE
CARDIOTOXIC
DOSE (mg/kg)
Mouse
(CD- 1)
F
Twice a week for 5 weeks with 2-week interval between 2nd and 3rd cycle of treatment. 77 0.67, 1.0, 1.5 6.7,10, 15 6.7
Mouse
(ICR Swiss)
F
Twice a week for 5 weeks with 2-week interval between 2nd and 3rd cycle of treatment 77 1.1, 2.2, 3.3 11,22,33 >11
Mouse
(ICR Swiss)
F
Twice a week for 5 weeks with 2-week interval between 2nd and 3rd cycle of treatment. 771 10<10
Mouse
(CD- 1 )
F
Twice a week for 4 or 5 weeks or once a week for 8 or 10 weeks. 77 0.45,0.6, 0.67,
0.9, 1.0, 1.35,
1.5, 2.0
3.6,4.8,6.7,
9,10,10.8,15, 20
7.2
Mouse
(C3H)
F
Once a week for 4 weeks. 58 0.8, 1.2 3.2, 4.8 >4.8

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