Mitoxantrone

Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and non-proliferating cultured human cells, suggesting lack of cell cycle phase specificity and activity against rapidly proliferating and slow-growing neoplasms. Mitoxantrone blocks the cell cycle in G2-phase leading to an increase of cellular RNA and polyploidy.

Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, tumour necrosis factor alpha, and interleukin-2.

Pharmacodynamic effects

Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its therapeutic efficacy has been reported in numerous malignancies. Its presumed mechanism of action in MS is immunosuppression.

Absorption

The pharmacokinetics of mitoxantrone in patients following single-dose intravenous administration can be characterised by a three-compartment model. In patients administered 15-90 mg/m², there is a linear relationship between dose and the area under the concentration curve (AUC). Plasma accumulation of active substance was not apparent when mitoxantrone was administered either daily for five days or as a single dose every three weeks.

Distribution

Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m². Plasma concentrations decrease rapidly during the first two hours and slowly thereafter. Mitoxantrone is 78% bound to plasma proteins. The fraction bound is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin. Mitoxantrone does not cross the blood-brain barrier. Distribution into testes is relatively low.

Biotransformation and elimination

The pathways leading to the metabolism of mitoxantrone have not been elucidated. Mitoxantrone is excreted slowly in urine and faeces as either unchanged active substance or as inactive metabolites. In human studies, only 10% and 18% of the dose were recovered in urine and faeces respectively as either active substance or metabolite during the 5-day period following administration of the medicinal product. Of the material recovered in urine, 65% was unchanged active substance. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates.

Many of the reported half-life values for the elimination phase are between 10 and 40 hours, but several other authors have reported much longer values of between 7 and 12 days. Differences in the estimates may be due to the availability of data at late times after doses, weighing of the data and assay sensitivity.

Special populations

Mitoxantrone clearance may be reduced by hepatic impairment.

There does not seem to be relevant differences in pharmacokinetics of mitoxantrone between elderly and young adult patients. The effect of gender, race, and renal impairment on mitoxantrone pharmacokinetics is unknown.

Mitoxantrone pharmacokinetics in the paediatric population is unknown.

Single and repeat toxicity studies were conducted in mouse, rat, dog, rabbits, and monkey. The haematopoietic system was the primary target organ of toxicity showing myelosuppression. Heart, kidney, gastrointestinal tract, and testes were additional targets. Tubular atrophy of the testes and decreased sperm counts were observed.

Mitoxantrone was mutagenic and clastogenic in all in vitro test systems and in rats in vivo. Carcinogenic effects were seen in rat and in male mice. Treatment of pregnant rats during the organogenesis period of gestation was associated with foetal growth retardation at doses >0.01 times the recommended human dose on an mg/m² basis. When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses >0.01 times the recommended human dose on an mg/m² basis. No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on an mg/m² basis). No effects were observed on pup development or fertility in the two generation study in rats.