Singapore Drugs Database

Indication

For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.

Mechanism of Action

Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established.

Pharmacokinetics

Absorption

Oral bioavailability is 34 to 48%.

Distribution

* 4.5 ± 2.8 L/kg [patients with hematologic malignancies] * 9 L/kg

Metabolism

Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate

Elimination

Clearance

* 978 +/- 422 mL/h/kg

Toxicity

Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.

Active Ingredient/Synonyms

(2R,3S,5R)-5-(6-amino-2-Chloropurin-9-yl)-2-(hydroxymethyl)oxolan-3-ol | 2-CdA | 2-Chloro-2'-deoxy-beta-adenosine | 2-Chloro-2'-deoxyadenosine | 2-chloro-6-amino-9-(2-Deoxy-beta-D-erythro-pentofuranosyl)purine | 2-chloro-Deoxyadenosine | 2-Chlorodeoxyadenosine | 2ClAdo | Cladribina | Cladribine | Cladribinum | CldAdo | Cladribine |