Source: Medicines Authority (MT) Revision Year: 2015 Publisher: 1 A Pharma GmbH, Keltenring 1+3, 82041 Oberhaching, Germany
Pharmacotherapeutic group: Antimetabolite (pyrimidine analogue)
ATC Code: L01BC01
Alexan contains the active ingredient cytarabine, an antimetabolite from the series of pyrimidine antagonists.
Cytarabine is a cell-cycle-phase-specific antineoplastic agent, which can only affect cells during the S-phase of cell division. It is converted intracellularly into cytarabine-5' triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that araCTP acts primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture.
Cytarabine is rapidly metabolised and is orally ineffective. Less than 20% of a dose administered orally is absorbed in the gastrointestinal tract.
In the event of continuous intravenous administration, virtually constant plasma levels are achieved.
After subcutaneous or intramuscular administration of cytarabine, peak plasma levels are achieved approximately 20 to 60 minutes after injection which are significantly lower than after intravenous administration.
Cytarabine serum levels can vary considerably from patient to patient for an identical dose. Some studies have shown that these variations could be linked to the clinical response: high serum levels guarantee the best chance of haematological remissions.
Cytarabine has a distribution volume of 0.7 l/kg. Cytarabine should be intrathecally administered as prophylaxis and in the treatment of CNS leukaemia, because intravenously administered cytarabine only crosses the blood-brain barrier in limited quantities. Intrathecal administration of cytarabine results in extremely low plasma levels.
Cytarabine is converted rapidly by deoxycitidine kinase and other nucleotidases into its active form (cytarabine-5' triphosphate) by phosphorylation in leukaemic blast cells and in healthy bone marrow. Metabolism into the inactive compound uracilarabinoside (1-beta-D-arabinofuranosyluracil) by means of cytidine deaminase activity takes place primarily in the liver, and to a lesser extent in the other tissues and blood.
It is assumed that the balance between kinase and deaminase levels can form an important factor in the determination of whether the cell is sensitive or resistant to cytarabine.
Binding to plasma protein is low (13.3%) with concentrations of 0.005-1 mg/l.
The percentage of bound drug was independent of the concentration within the limits indicated.
After a rapid intravenous infusion of cytarabine, biphasic elimination from the blood takes place. There is an initial distribution phase with a half life of approx. 10 minutes, followed by a secondary elimination phase with a half life of 1-3 hours.
After 24 hours, approx. 80% of the administered cytarabine is found in the urine, 90% of which is excreted as inactivated metabolite and 10% as unchanged cytarabine.
Due to the low cytarabine deaminase activity in the cerebrospinal fluid, cytarabine has an elimination half life in the CNS of 3-3.5 hours.
Studies have reported that cytarabine is genotoxic (in vivo and in vitro) as well as embryotoxic and teratogenic, if exposed to pregnant mammals during the organogenesis in clinically relevant dosage regimen.
It is also reported that cytarabine causes damage to the developing brain if administered to newborn mammals (period equivalent to third trimester in humans) and increases the frequency of abnormal spermatozoa in vivo in mice.
It has been shown that cytarabine is carcinogenic in animals. The possibility of a comparable effect must be taken into account when determining the long-term strategy for the patient.
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