Mitoxantrone

Structural formula
General
Non-proprietary name	Mitoxantrone
other names	1,4-dihydroxy-5,8-bis- [2- (2-hydroxyethylamino) ethylamino] anthracene-9,10-dione ( IUPAC )
Molecular formula	C 22 H 28 N 4 O 6
External identifiers / databases
CAS number 65271-80-9 70476-82-3 (di hydrochloride ) PubChem 4212 ChemSpider 4067 DrugBank DB01204 Wikidata Q239426
Drug information
ATC code	L01 DB07
Drug class	Antibiotics with a cytostatic effect
Mechanism of action	Topoisomerase II - inhibitor
properties
Molar mass	444.48 g · mol -1
Physical state	firmly
Melting point	160-162 ° C ; 203-205 ° C (dihydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 360 P: 201-308 + 313
Toxicological data	6.6 mg kg −1 ( LD 50 ,  mouse ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Mitoxantrone is a cytostatically active drug . It is used for cancer therapy and for the treatment of multiple sclerosis (MS).

Origin and manufacture

Mitoxantrone is a cytotoxic antibiotic belonging to the anthracenedione group .

Mechanism of action

Mitoxantrone attaches itself to the DNA by forming hydrogen bonds (intercalation). Mitoxantrone then causes cross-links and strand breaks in the DNA. Mitoxantrone also hinders the formation of RNA and strongly inhibits topoisomerase II , which is responsible for the de-spiralization and repair of damaged DNA. Mitoxantrone has a cytotoxic (cell-toxic) effect on dividing and resting cells , which means that it is effective regardless of the cell cycle .

The effects of mitoxantrone lead to an inhibition of the growth of T and B lymphocytes and macrophages . In the latter, the presentation of antigens and the secretion of interferon -γ, tumor necrosis factor -α and interleukin-2 are suppressed.

Although mitoxantrone is structurally related to the anthracycline antibiotics doxorubicin , daunorubicin , idarubicin, and epirubicin , unlike them, it cannot generate quinone-like free radicals.

Pharmacokinetics

• Bioavailability : 100% as it is administered intravenously only
• Protein binding: 78%
• Volume of distribution: 1875-2248 l / m ²
• Plasma half-life : α-phase 0.14 h; β phase 3.1 h; γ phase 36-215 h

The pharmacokinetics of mitoxantrone corresponds to a 3-compartment model (3-phase model: alpha, beta and gamma phase).

Uptake and bioavailability

The tissue distribution of mitoxantrone after a single intravenous administration is very high. The volume of distribution is over 1000 L / m ² . The tissue concentrations of mitoxantrone exceed the concentrations in plasma during the gamma phase. In patients with a dose of 15–90 mg / m ^{2 there} is a linear relationship between the dose and the area under the concentration-time curve (area under curve, AUC).

Metabolism (metabolism)

Mitoxantrone is not metabolized by the cytochrome P450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. However, mitoxantrone is a weak inducer of the cytochrome P450 enzyme 2E1.

Elimination

The mean half-life for mitoxantrone is 6–12 minutes in the alpha phase, 1.1–3.1 hours in the beta phase and 23–215 hours (median 75 hours) in the gamma phase (also known as the terminal elimination half-life ). Mitoxantrone is excreted in the urine and stool as unchanged substance or inactive metabolites: 11% of a dose of mitoxantrone was excreted in the urine within 5 days, 25% in the stool. 65% of the substance detectable in the urine consisted of unchanged mitoxantrone, the remaining 35% consisted of monocarboxyl and dicarboxyl derivatives and glucuronide conjugates.

application areas

Mitoxantrone is used both as a cytostatic agent in the treatment of cancer and as an immunosuppressant in the treatment of multiple sclerosis.

Adults

• Acute myeloid leukemia (AML): In the treatment of acute myeloid leukemia, mitoxantrone is usually given in combination with cytarabine as so-called HAM or haM blocks. These blocks are effective in combating AML, but also have side effects, in particular the bone marrow toxicity is high.
• Multiple sclerosis (MS): Mitoxantrone is used in the therapy of secondary chronic MS and against relapsing MS with rapid progression . Studies have shown that mitoxantrone significantly reduces the relapse rate. In addition, the progression of the disease is slowed down by about 30% in both relapsing and secondary chronic disease.
• Breast cancer (metastatic)
• Prostate cancer (advanced)
• Non-Hodgkin lymphoma (NHL)

Children and young people

• Acute myeloid leukemia (AML): In the treatment of acute myeloid leukemia, mitoxantrone is usually given in combination with cytarabine as so-called HAM or haM blocks. These blocks are effective in combating AML, but also have side effects, in particular the bone marrow toxicity is high.
• Multiple sclerosis (MS): The use of mitoxantrone in multiple sclerosis in children and adolescents is based on experience in adulthood. The use of mitoxantrone in children and adolescents with multiple sclerosis is experimental despite previous experience - there is no approval for this indication in children and adolescents.

Dose and administration

Mitoxantrone is given intravenously as an infusion. As an accompanying medication against any nausea, z. B. Ondansetron also administered intravenously.

Adults

• Multiple sclerosis (MS): 5–12 mg / m ² body surface area (BSA) per single dose. 1 single dose is given in one day. The single doses are repeated every 12 weeks. The duration of therapy is limited by the cumulative maximum dose to 24–36 months or, alternatively, 120–140 mg / m ² BSA. An earlier limitation by the manufacturer to the cumulative total dose of 100 mg / m ^{2 head body} was lifted after intervention by the Multiple Sclerosis Therapy Consensus Group (MSTKG) of the German Multiple Sclerosis Society (DMSG).
• Acute myeloid leukemia (AML): 12 mg / m ² BSA per single dose. A single dose is given in one day. The duration of treatment is three days (three single doses).

Children and young people

• Multiple Sclerosis (MS). 5–12 mg / m ² BSA per single dose. 1 single dose is given in one day. The single doses are repeated every 6-12 weeks. The duration of therapy is limited by the cumulative maximum dose to 24–36 months or, alternatively, 96 mg / m ² BSA.
• Acute myeloid leukemia (AML). 12 mg / m ² BSA per single dose. 1 single dose is given in one day. The duration of treatment is three days (three single doses) f

In patients with Down syndrome and AML, the dose is reduced: 8 mg / m ² BSA per single dose. A single dose is given in one day. The duration of treatment is three days (three single doses).

Side effects

It occurs frequently with the administration of mitoxantrone

• Nausea and vomiting
• Loss of appetite ( anorexia )
• Hair loss ( alopecia )
• Damage to the mucous membrane ( mucositis ).
• Bone marrow toxicity: Mitoxantrone has a markedly toxic effect on the bone marrow, which can result in anemia , thrombopenia and leukopenia . Ten days after the administration of mitoxantrone, the nadir (low point) of the blood cell count is reached, after 21 days the bone marrow (and the blood count ) usually recover . Depending on the combination with other cytostatics ( e.g. cytarabine ), this side effect can be more pronounced or last longer.
• Infections due to leukopenia and neutropenia (for example in the form of respiratory infections , urinary tract infections )
• Cardiotoxicity ( damage to the heart ): Like the structurally related anthracyclines, mitoxantrone has a significant cardiotoxic effect. On the one hand, temporary (reversible) cardiac arrhythmias can occur. On the other hand, and significantly more serious, is the occurrence of mitoxantrone-related toxic cardiomyopathy (heart muscle damage). This usually leads to irreversible heart failure , which sometimes requires a heart transplant . As a safety measure for the early detection of cardiac muscle damage, regular echocardiography (heart ultrasound), at least once a year, is urgently recommended. There is also a total cumulative dose that should not be exceeded. The substance should be used with particular caution in patients with known heart diseases .
• Local irritation: If mitoxantrone is accidentally applied next to the vein (paravasally), it comes to a painful tissue irritation with only slowly fading blue skin discoloration.
• Treatment-associated leukemia (secondary leukemia as secondary malignancy) can occur as a result of treatment with mitoxantrone, especially in combination with etoposide and teniposide . This occurs in 0.05–0.1% of patients treated with mitoxantrone.

Contraindications and Precautions

Absolute contraindications

• Hypersensitivity to mitoxantrone
• pregnancy
• Lactation
• Present severe myelosuppression
• Intrathecal use
• Mitoxantrone is not indicated for intra-arterial injection

Precautions for use

• Heart failure
• Infections should be treated prior to treatment with mitoxantrone
• Vaccination with live vaccines is generally not recommended
• Elimination may be reduced in patients with severe hepatic insufficiency and mitoxantrone should be used with caution in these patients.

costs

The cost of an infusion with mitoxantrone varies depending on the patient's stature and the dosage. The cost of 12 mg of the drug Ralenova ^® is around EUR 200.

Trade names

Monopreparations

Ebexantron (A), Haemato-tron (D), Novantron (D, A, CH), Onkotrone (D), Ralenova (D), various generics (D, A, CH)

Web links

• British Columbia Cancer Agency Monograph As of December 1, 2002. Open to the public.
• US package insert Mitoxantrone (PDF; 1.4 MB) Status: October 13, 2000. Freely accessible.

Individual evidence

1. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 1073, ISBN 978-0-911910-00-1 .
2. ↑ Entry on mitoxantrone. In: Römpp Online . Georg Thieme Verlag, accessed on June 25, 2019.
3. ↑ ^{a b} Datasheet Mitoxantrone dihydrochloride from Sigma-Aldrich , accessed on April 10, 2011 ( PDF ).
4. ^ Entry on Mitoxantrone in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ↑ Summary of the product characteristics (product information) from Mitoxantron-GRY ^® - GRY-Pharma GmbH .

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !