Brands, Medical Use, Clinical Data
- Antineoplastic agents
- Purine analogues
- Solution for intravenous infusion (1 mg/mL, supplied in a 20 mL, single-use vial)
Brands / Synonyms
For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.
Clofarabine is a purine nucleoside antimetabolite. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells also may be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells.
Mechanism of Action
Clofarabine is metabolized intracellularly to the active 5’-triphosphate metabolite. This metabolite inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5’-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death.
There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash.
Biotrnasformation / Drug Metabolism
Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine.
Contraindicated in pregnancy or planned pregnancy, breast-feeding, liver problems, and kidney problems.
Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the
in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of
clofarabine. The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied.
Drug/Laboratory Tests Interactions
There are no known clinically significant interactions of CLOLARÔ with
other medications or laboratory tests. No formal drug/laboratory test interaction studies have been conducted with