CLOFAZIMINE

Indications

• Induction of remission in acute myeloblastic leukaemia
• Relapsed or refractory acute lymphoblastic leukaemia
• Lymphomatous meningitis

Dosage

Adults: Consult local protocol for specific dosing guidelines based on the clinical scenario, typically

Mechanism of action

Clofarabine is metabolized intracellularly to its active forms, primarily the 5'-monophosphate and 5'-triphosphate metabolites. These metabolites inhibit DNA synthesis by obstructing ribonucleotide reductase activity, terminating DNA chain elongation, and inhibiting DNA repair through competitive inhibition of DNA polymerases. This results in a depletion of the intracellular deoxynucleotide triphosphate pool, enhancing clofarabine triphosphate incorporation into DNA, which intensifies the inhibition of DNA synthesis. Additionally, clofarabine 5'-triphosphate disrupts mitochondrial membrane integrity, promoting apoptosis by releasing pro-apoptotic factors.

Pharmacodynamics

Clofarabine's unique structure, with a chlorine in the purine ring and a fluorine in the ribose, allows it to effectively interfere with nucleic acid synthesis, leading to the destruction of cancer cells. This antimetabolite action results in the inhibition of DNA and RNA synthesis, thereby halting the proliferation of neoplastic cells. While effective against cancer cells, clofarabine may also affect normal cells, leading to various side effects.

Pharmacokinetics

Clofarabine is administered intravenously and is rapidly distributed throughout the body. It undergoes intracellular metabolism to its active forms and is excreted mainly by the kidneys. In patients with renal impairment, dose adjustments may be necessary to prevent accumulation and toxicity. The pharmacokinetics can be influenced by factors such as renal and hepatic function, necessitating careful monitoring in affected patients.

Contra-indications

• Severe renal impairment
• Severe hepatic impairment
• Known hypersensitivity to clofarabine or any of its components

Adverse effects

• Alopecia
• Anxiety
• Appetite loss
• Capillary leak syndrome
• Chills
• Decreased performance in skilled tasks
• Dizziness
• Drowsiness
• Diarrhea
• Vomiting
• Vision disorders
• Fatigue
• Fever
• Gastrointestinal discomfort
• Headache
• Infection
• Paralysis
• Hepatic disorders
• Arrhythmias
• Hyperbilirubinaemia
• Hypersensitivity reactions

Interactions

• Live vaccines (increased risk of generalized infection, possibly life-threatening)

Precautions

• Caution in mild to moderate renal impairment
• Caution in mild to moderate hepatic impairment
• Use with caution in patients with cardiac disease
• Patients should be counseled on the effects on driving and performance of skilled tasks

Pregnancy

Manufacturer advises to avoid use due to teratogenic effects observed in animal studies.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a refrigerator at 2–8°C.

Formulations

• Clofarabine 1 mg per 1 ml solution for infusion
• Clofarabine 20 mg/20 ml concentrate for solution for infusion

Mechanism of action

Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. 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.

Pharmacodynamics

Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also 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.