Idarubicin Hydrochloride Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Idarubicin Hydrochloride Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Acute Myeloid Leukemia
Class: Antineoplastic detoxifying agents, Antineoplastics
Form: Liquid solution, Intravenous (IV)
Ingredients: Idarubicin hydrochloride, Glycerin, Hydrochloric acid, Water for Injection

Pharmaceutical Information

Drug Substance

Proper name: Idarubicin Hydrochloride, USP
Chemical name: 5,12-Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S-cis)-.

(1S, 3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside, hydrochloride
Molecular formula and molecular mass: C26H27NO9.HCl; 533.95
Structural formula:

 


Physicochemical properties: Idarubicin hydrochloride is a DNA intercalating analog of daunorubicin. The modification in position 4 of the aglycone, gives the compound a high lipophilicity.

It is an orange crystalline powder. It is freely soluble in DMF, soluble in methanol, sparingly soluble in water, very slightly soluble in tetrahydrofuran and practically insoluble in choloroform, insoluble in acetone and ethyl ether. Its melting point is 181 °C - 185 °C.

Clinical Trials

Four prospective randomized studies have been conducted to compare the efficacy and safety of idarubicin (IDR) to that of daunorubicin (DNR), each in combination with cytarabine as induction therapy in previously untreated adult patients with acute non-lymphocytic leukemia (ANLL). These data are summarized in the following table:

  Inductiona Regimen Dose in mg/m2 - Daily x 3 Days Complete Remission Rate, All Pts Randomized Median Survival All Pts Randomized
U.S. Studies DR DNR IDR DNR IDR DNR
1. MSKCC*
(Age ≤ 60 years)
12b 50b 48/60+
(80%)
35/60
(58%)
19.7 months+ 13.5 months
2. SEG**
(Age ≥ 15 years)
12c 45c 75/105+
(71%)
65/113
(58%)
297 days 277 days
3. U.S.Multicenter
(Age ≥ 18 years)
13c 45c 68/101
(67%)
65/113
(58%)
12.9 months+ 8.7 months
Italian study
4. GIMEMA***
(Age ≥ 55 years)
12c 45c 50/124
(40%)
49/125
(39%)
87 days 169 days

* Memorial Sloan Kettering Cancer Center
** Southeastern Cancer Study Group
*** Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto
+ Overall p < 0.05, unadjusted for prognostic factors or multiple endpoints
a Patients who had persistent leukemia after the first induction course received a second course
b Cytarabine 25 mg/m2 bolus i.v. followed by 200 mg/m2 daily x 5 days by continuous infusion
c Cytarabine 100 mg/m2 daily x 7 days by continuous infusion

There is no consensus regarding optional regimens to be used for consolidation; however, the following consolidation regimens were used in U.S. controlled trials. Patients received the same anthracycline for consolidation as was used for induction.

Studies 1 and 3 utilized 2 courses of consolidation therapy consisting of idarubicin 12 or 13 mg/m2 daily for 2 days, respectively (or DNR 50 or 45 mg/m2 daily for 2 days), and cytarabine, either 25 mg/m2 by i.v. bolus followed by 200 mg/m2 daily by continuous infusion for 4 days (Study 1), or 100 mg/m2 daily for 5 days by continuous infusion (Study 3). A rest period of 4 to 6 weeks is recommended prior to initiation of consolidation and between the courses. Hematologic recovery is mandatory prior to initiation of each consolidation course.

Study 2 utilized 3 consolidation courses, administered at intervals of 21 days or upon hematologic recovery. Each course consisted of idarubicin 15 mg/m2 i.v. for 1 dose (or DNR 50 mg/m2 i.v. for 1 dose), cytarabine 100 mg/m2 every 12 hours for 10 doses and 6-thioguanine 100 mg/m2 orally for 10 doses. If severe myelosuppression occurred, subsequent courses were given with 25% reduction in the doses of all drugs. In addition, this study included 4 courses of maintenance therapy (2 days of the same anthracycline as was used in induction and 5 days of cytarabine).

Toxicities and duration of aplasia were similar during induction on the 2 arms in the U.S. studies except for an increase in mucositis on the IDR arm in one study. During consolidation, duration of aplasia on the IDR arm was longer in all 3 studies and mucositis was more frequent in 2 studies. During consolidation, transfusion requirements were higher on the IDR arm in the 2 studies in which they were tabulated, and patients on the IDR arm in Study 3 spent more days on i.v. antibiotics (Study 3 used a higher dose of idarubicin).

The benefit of consolidation and maintenance therapy in prolonging the duration of remission and survival is not proven.

Intensive maintenance with idarubicin is not recommended in view of the considerable toxicity (including deaths in remission) experienced by patients during the maintenance phase of Study 2.

A higher induction death rate was noted in patients on the IDR arm in the Italian trial. Since this was not noted in patients of similar age in the U.S. trials, one may speculate that it was due to a difference in the level of supportive care.

Detailed Pharmacology

The antitumor activity of idarubicin has been compared with that of daunorubicin against various murine leukemias. After intraperitoneal or intravenous treatment, idarubicin exhibited a comparable anti-leukemic activity and was more potent (approximately 5 - 6 fold) than the parent compound daunorubicin in the P388 and L1210 systems at the optimal doses. Conversely, in the EL-4 lymphoma model, idarubicin given intravenously, displayed a significantly better therapeutic effect than daunorubicin with a similar potency difference. The activity of idarubicin was also evaluated against disseminated (intravenously-transplanted) murine L1210, and Gross leukemias. Against advanced L1210, idarubicin was capable of significantly prolonging survival time whereas daunorubicin was inactive even at 10-fold higher doses. The effectiveness and the higher potency of idarubicin were also confirmed in the Gross leukemia model.

The antineoplastic efficacy of intravenous idarubicin has also been tested against a number of solid murine tumors. Idarubicin was only partially active against murine solid tumors. Specifically, idarubicin was as effective as daunorubicin on S180 and less active than doxorubicin against mammary carcinoma. In the Lewis lung carcinoma model, idarubicin showed antitumor activity greater than daunorubicin and comparable to doxorubicin, but at a toxic dose (33% of toxic deaths). Against the M5 reticulosarcoma model, idarubicin was inactive, as were daunorubicin and doxorubicin. In addition, idarubicin showed a lower activity than doxorubicin against a number of human solid tumors xenografted into nude mice. It is known however that solid murine tumors have only a relatively low level of predictiveness for clinical activity.

On the basis of the in vitro data which suggested incomplete cross -resistance between idarubicin and doxorubicin or daunorubicin, the in vivo activity of idarubicin was also tested against a P388/DX leukemia subline. However, given in single intraperitoneal or intravenous doses, idarubicin was not significantly effective against this highly doxorubicin-resistant tumor.

In vivo, idarubicinol exhibited clear antitumour activity after intravenous and intraperitoneal treatment in mice bearing ascitic P388 or disseminated Gross leukemia, although its potency and activity were somewhat lower with respect to the parent drug.

Idarubicin was studied intravenously in mice and rats for other, possible, non- antitumoral activities. It was devoid of central nervous system activity (Irwin's behaviour test, body temperature, spontaneous motility, neuromuscular coordination) even at doses much higher than the LD50.

The acute effect on the cardiovascular system in the rat is considered to be moderate, since a slight decrease in arterial pressure and in heart rate was seen only at doses equal to the LD50 which starts 1 hr after treatment. In another study, rats were observed for 36 days after a single intravenous injection of 1 mg/kg. Idarubicin did not alter arterial pressure, heart rate or duration of QRS complexes and only showed prolongation of Q-T interval on the last day.

By comparison, doxorubicin, given at an equitoxic dose of 5 mg/kg, did not alter the arterial pressure, but induced a progressive increase in the heart rate, a slight increase in the duration of the QRS complexes and a much more marked increase in the Q-T interval. Since the prolongation of the Q-T interval is a well-known aspect of anthracycline cardiotoxicity, the results of this study confirm that idarubicin is less cardiotoxic than doxorubicin.

In a series of in vivo and in vitro studies, idarubicin proved to be devoid of effects on the autonomic nervous system, as shown by the absence of interference with the mediators used. Intravenously in the rat, idarubicin induced a marked slowing of gastric emptying: this was already evident at the lowest dose tested, 0.625 mg/kg.

With regard to immunological activity, idarubicin had an inhibitory effect on antibody production (IgM and IgG) at 1/4 to 1/2 of the LD50 values, when administered concomitantly with, or after the antigen. This effect was similar to that of doxorubicin given at approximately equitoxic doses. However, unlike doxorubicin, idarubicin does not inhibit the production of antibodies when administered before the antigen. In the test of delayed hypersensitivity, idarubicin showed a slight inhibitory action, while daunorubicin was more active and doxorubicin proved to be inactive. Idarubicin delays skin graft rejection only if administered repeatedly.

In contrast with daunorubicin, idarubicin was found to be significantly more active on an immunogenic leukemia subline (L1210 Ha) than on a non-immunogenic subline (L1210 Cr), probably due to idarubicin interfering less with the antitumour resistance mechanism than daunorubicin.

Toxicology

In clinical oncology and in particular in the treatment of leukemia, which is and must be particularly aggressive, the maximum tolerable doses are normally used, and are, therefore, of the order of magnitude of the LD10 values, expressed in mg/m2. These values are useful only when degree of exposure as expressed by the area under the curve (AUC) is also taken into consideration.

In the mouse, the LD10 of idarubicin was equal to 12.35 mg/m2. The mouse:man exposure ratio at the same doses is estimated at approximately 5:1 to 10:1. In addition, the metabolism of idarubicin as compared with the less toxic idarubicinol, is more extensive in man than in the mouse. Idarubicinol was shown to be considerably less toxic than idarubicin. These results offer a considerably wide margin of safety for clinical use of idarubicin. Studies in the mouse also indicate that idarubicin is less cardiotoxic than either daunorubicin or doxorubicin when evaluated at dose ratios which result in similar antileukemic efficacy for the 3 drugs.

Studies were carried out with idarubicin in the rat and dog under the same experimental conditions in parallel with doxorubicin. In the rat, idarubicin was approximately twice as toxic as doxorubicin and had a greater effect on the hematolymphopoietic system. At the same time, idarubicin had a more limited effect on the myocardial, renal, hepatic and testicular parenchyma. In the dog, idarubicin was slightly more toxic than doxorubicin due to greater hematological effect, whereas doxorubicin had a greater effect on the renal, hepatic, testicular and myocardial parenchyma. The cardiotoxicity of idarubicin, when compared to its relative toxicity and activity, proved to be lower than that of doxorubicin.

Teratology

Idarubicin is not teratogenic in the rabbit, even at toxic doses. However, it is teratogenic in the rat at doses of 0.1 - 0.2 mg/kg/day or 0.7 - 1.4 mg/m2.

Carcinogenicity

Idarubicin was studied on female Sprague-Dawley rats treated with a single intravenous dose of 1.8 mg/kg in comparison with doxorubicin administered as an equitoxic dose of 5 mg/kg. Results indicate that idarubicin must be considered to be carcinogenic, a characteristic which it shares with most other antitumoral drugs.