Idarubicin

Abstract

Idarubicin is a 4-demethoxy-anthracycline analogue of daunorubicin which, when administered intravenously in combination withcytarabine,hastherapeutic efficacy superior to that of standard induction and salvage treatment regimens in acute myelogenous leukaemia. Idarubicin alone or in combination regimens has also been effective in limited studies in patients with other acute leukaemias, advanced breast cancer, multiple myeloma and non-Hodgkin’s lymphoma. Idarubicin is more lipophilic than its parent drug daunorubicin. It intercalates DNA, induces DNA strand breaks and delays cell cycle progression. Leucopenia is often dose-limiting in patients with solid tumours treated with idarubicin, and most other adverse effects are similar in incidence and severity to those experienced with other anthracycline cytotoxic agents, except for alopecia which appears to occur with a reduced incidence and severity. Cardiotoxic effects have been reported with idarubicin as with other anthracyclines, but animal data and preliminary clinical findings suggest the possibility of reduced cardiotoxicity with idarubicin — a potentially important advantage if confirmed on further study. A maximum cumulative dose of idarubicin beyond which the incidence of cardiotoxicity rapidly increases has not been determined. Thus, intravenous idarubicin is a useful alternative to other anthracyclines (particularly in combination with cytarabine) in the treatment of acute myelogenous leukaemia, and there is some evidence that it is less cardiotoxic than other anthracycline drugs. Further studies are required to establish the use of intravenous idarubicin as a replacement for other intravenous anthracyclines, especially its effect on response duration and survival, and to confirm the evidence of reduced cardiotoxic effects. The role of idarubicin as consolidation and maintenance therapy for various malignancies requires further investigation, as does the potential use of oral idarubicin which is currently under development. The absence of a methoxyl group at position 4 of idarubicin’s anthracycline structure results in an increased lipophilicity and rate of cellular uptake compared with the related compound daunorubicin. Idarubicin is 10-fold more cytotoxic than daunorubicin, with greater activity than daunorubicin or doxorubiein (adriamycin) against cultured human cancer cells. The primary metabolite, idarubicinol (4-demethoxy-daunorubicinol), demonstrated similar activity to idarubicin in vitro Both idarubicin and the metabolite showed antitumour activity superior to that of doxorubicin and at least equivalent to that of daunorubicin in experimental leukaemia models in vivo when administered intravenously or orally. Importantly, the ratio of cardiotoxic to antitumour dose for idarubicin exceeded that for daunorubicin and doxorubicin. Idarubicin intercalates DNA, disrupting nucleic acid synthesis. It induces DNA strand breaks by inhibiting DNA topoisomerase II and generating free radicals, arresting cells in the G₂ phase of the cell cycle. Animal toxicity tests demonstrated decreased cardiotoxicity of idarubicin compared with daunorubicin and doxorubiein; haematolymphopoietic arid gastrointestinal symptoms were consistent with those observed with other cytotoxic agents. The pharmacokinetic properties of idarubicin following oral or intravenous administration have been studied in patients with solid tumours or acute leukaemias. Bioavailability of orally administered idarubicin varied widely between patients and studies, although a mean of about 30% was generally observed. Idarubicin is rapidly converted by the liver to its only detected metabolite, idarubicinol, and higher concentrations of idarubicinol are produced following oral rather than intravenous dosing, probably due to first pass metabolism in the liver. Biphasic and triphasic plasma clearance of idarubicin have been observed. Following intravenous administration, initial phase half-life was 9 to 30 minutes, intermediate phase 3.2 to 27 hours and elimination phase 6 to 35 hours. Plasma concentrations of idarubicinol exceeded those of idarubicin, and the metabolite accumulated over 3 consecutive days of idarubicin 10 mg/m² 4-hour infusions. Idarubicin has a large volume of distribution (up to 1889 L/m²), and concentration independent mean plasma protein binding of idarubicin and idarubicinol were 97 and 94%, respectively. Idarubicin was undetectable in plasma (less than 2 Mg/L) 24 hours after oral administration of idarubicin 30 to 70 mg/m², and 72 hours following intravenous administration of idarubicin 12.5 to 15 mg/m². The metabolite was still detectable in plasma for at least 72 hours following intravenous idarubicin 15 mg/m² and up to 7 days following oral administration of idarubicin 15 mg/m². Total body clearance rates for idarubicin of 30 to 122 L/m²/h were reported, and less than 5% of the delivered idarubicin dose was recovered as idarubicin or its metabolite in urine over 24 or 96 hours. Dosage reduction should not be necessary in patients with impaired renal function but may be required in patients with hepatic impairment. Intravenous idarubicin, in combination with cytarabine, has demonstrated therapeutic efficacy in patients with relapsed or refractory acute myelogenous leukaemia (complete response rates of 24 to 70%). Response duration was short although 1 patient remained in complete remission for longer than 14 months with idarubicin plus cytarabine consolidation therapy. As induction treatment for patients with acute myelogenous leukaemia, intravenous idarubicin plus cytarabine was at least as effective as daunorubicin plus cytarabine, with complete response rates being significantly higher with the idarubicin regimen in several studies. Mean duration of response tended to be longer in idarubicin plus cytarabine recipients, the difference between groups reaching statistical significance in 2 studies (for example 30 vs 13 months, p=0.012). Mean duration of survival was also significantly longer in idarubicin plus cytarabine recipients compared with daunorubicin plus cytarabine recipients in 2 of 3 large US comparative studies in previously untreated acute myelogenous leukaemia patients (probability of survival at 18 months 48 vs 28% and 35 vs 23%, p 2 intravenously. Importantly, as suggested by animal studies, in clinical trials there was some evidence for a reduction of cardiotoxicity compared with doxorubicin; however, a maximum cumulative noncardiotoxic dose of idarubicin has not yet been determined. The incidence and severity of other adverse effects were similar in intravenous idarubicin-and daunorubicin-treated patients. Leucopenia was dose-limiting in patients with solid tumours receiving oral idarubicin 50 to 60 mg/m² and the incidence of alopecia appeared to be reduced in patients receiving oral idarubicin. Further comparative studies are required to verify these findings. For patients with acute myelogenous leukaemia, the recommended intravenous dose of idarubicin for induction therapy is 12 mg/m² daily for 3 days by slow (10 to 15 minutes) infusion, in combination with cytarabine 100 mg/m² daily by continuous infusion for 7 days or cytarabine 25 mg/m² intravenous bolus followed by 200 mg/m² daily for 5 days continuous infusion. A dose reduction should be considered in patients with hepatic impairment but may not be required in patients with compromised renal function. Dosage recommendations for children are not currently available and intravenous idarubicin 8 mg/m² for 5 days has been successfully used with cytarabine in the elderly. Idarubicin should not be administered to patients with pre-existing bone marrow suppression, heart disease or those who have received high cumulative doses of other anthracyclines or potentially cardiotoxic drugs. Cardiac monitoring is recommended in all patients and regular blood counts and hepatic and renal function tests should be performed. Oral administration remains experimental and dosage guidelines are not currently available.