Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, UK
Pharmacotherapeutic group: Antineoplastic agent
ATC code: L01DB02
The active ingredient of DaunoXome is daunorubicin, a cytotoxic anthracycline antibiotic isolated from Streptomyces coeruleorubidus. The exact mechanism of the antitumour activity of daunorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication. Daunorubicin also has antibacterial and immunosuppressive properties.
DaunoXome is a liposomal preparation of daunorubicin formulated to prolong circulation time and to maximise the selectivity of daunorubicin for tumors. While in the circulation, the DaunoXome formulation helps to protect the entrapped daunorubicin from chemical and enzymatic degradation, minimises protein binding, and generally decreases uptake by normal (non-reticuloendothelial system) tissues.
Tumour selectivity of DaunoXome has been demonstrated for transplanted tumours in animal models. The exact mechanism by which DaunoXome is able to deliver daunorubicin to solid tumours in situ is not known. However, it is believed to be a function of increased permeability of the tumour neovasculature to some particulates in the size range of DaunoXome. Once within the tumour environment, DaunoXome vesicles enter the tumour cells intact, after which liposomal disruption occurs with intracellular release of free daunorubicin. Pharmacokinetic studies also show measurable levels of free daunorubicin in plasma, which may have an additional anti-tumour effect. Results from in vivo therapeutic studies in mice, i.e., antitumour activity measured as increased median survival time and by reduced tumour size, have shown that DaunoXome has improved efficacy compared with daunorubicin at optimal doses. Clinical trials comparing liposomal and conventional daunorubicin have not been conducted.
Following the administration of DaunoXome, daunorubicin is present in plasma bound to liposomes and as free (protein-bound and non-protein-bound) drug.
The pharmacokinetic data of free daunorubicin is sparse and also somewhat deficient as analytical methods could not distinguish between daunorubicin and daunorubicinol. Following administration of conventional daunorubicin (80 mg/m²) as an intravenous bolus, plasma levels were approximately 0.4+0.6 µg/ml after 15 minutes. The levels fell below 0.1 µg/ml within approximately 24-36 hours. The volume of distribution was 1055±235 l; daunorubicin exhibits extensive tissue binding. Clearance was approximately 223 ml/min, AUC approximately 10.3 µg.hr/ml. The plasma concentration-time curve shows a biphasic process; the slow elimination is probably due to slow release from the tissue binding sites. A small amount was excreted through the urine; Daunorubicin is probably largely excreted through a biliary pathway.
DaunoXome was administered as an intravenous infusion over 30 minutes in doses from 10 to 80 mg/m². The increase in AUC of total daunorubicin levels was somewhat greater than proportional to dose. Average maximum levels of total daunorubicin following 40 mg/m² were 18 µg/ml (range 15-22 µg/ml). Clearance for total levels was approximately 10 ml/min (range 7-15). The steady-state volume of distribution was around 4 l (range 2-6 l). Mean terminal half-life was 4 hours (range 3-6 hours). Maximum daunorubicinol levels were below 0.3 µg/ml following the IV administration of 40 mg/m² DaunoXome.
The exposure, expressed as the AUC of total daunorubicin levels, following administration of 80 mg/m² as DaunoXome was approximately 36-fold increased as compared with the AUC after administration of 80 mg/m² as conventional daunorubicin.
Daunorubicin is mutagenic both in vitro and in vivo, and carcinogenic in vivo. A high incidence of mammary tumours was observed in rats treated with daunorubicin. Although no such studies have been conducted with DaunoXome, it is most likely that DaunoXome will have a similar mutagenic potential.
In experiments in rats, DaunoXome and daunorubicin have shown some renal toxicity; however, renal damage is not documented in the clinical use of daunorubicin. In experiments with mice, a cardiotoxic effect of DaunoXome was documented; in clinical practice however DaunoXome has so far proven less cardiotoxic than daunorubicin.
In mice, single IV doses of DaunoXome did not increase the myelosuppressive activity compared with equivalent doses of free daunorubicin.
Studies to evaluate the effects of liposomal daunorubicin on fertility have not been performed; however, the active ingredient, daunorubicin, caused testicular atrophy and total aplasia of spermatocytes in the seminiferous tubules in male dogs administered 0.25 mg/kg per day (approximately eight times the recommended human dose on a mg/m² basis).
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