tely 0.25 was observed in cancer patients.
Elimination
Cladribine estimated terminal half-life is approximately 1 day. The intracellular half-life of thecladribine phosphorylated metabolites cladribine monophosphate (Cd-AMP) is 15 hours and CdATPis 10 hours. Cladribine estimated median apparent renal clearance is 22.2 liter per hour andnon-renal clearance is 23.4 liter per hour.
Metabolism
Cladribine is a prodrug that is phosphorylated to Cd-AMP by deoxycytidine kinase (and also bydeoxyguanosine kinase in the mitochondria) in lymphocytes. Cd-AMP is further phosphorylatedto cladribine diphosphate (Cd-ADP) and the active moiety Cd-ATP. The dephosphorylation anddeactivation of Cd-AMP is catalyzed by cytoplasmic 5’-nucleotidase (5’-NTase).
The metabolism of cladribine in whole blood has not been fully characterized. However,extensive whole blood and negligible hepatic enzyme metabolism was observed, in vitro.
Excretion
After administration of 10 mg oral cladribine in MS patients, 28.5 [20] (mean [SD]) percent ofthe dose was excreted unchanged via the renal route. Renal clearance exceeded the glomerularfiltration rate, indicating active renal secretion of cladribine.
Specific Populations
No studies have been conducted to eva luate the pharmacokinetics of cladribine in elderly or inpatients with renal or hepatic impairment.
There were no clinically significant differences in the pharmacokinetics of cladribine based onage (range 18 to 65 years) or gender. The effect of hepatic impairment on the pharmacokineticsof cladribine is unknown.
Patients with Renal Impairment
Renal clearance of cladribine was shown to be dependent on creatinine clearance (CLCR). Nodedicated studies have been conducted in patients with renal impairment, however patients withmild renal impairment (CLCR of 60 mL to below 90 mL per minute) were included in Study 1. pooled pharmacokinetic analysis estimated a decrease of 18% in total clearance in a typicalsubject with a CLCR of 65 mL per minute leading to an increase in cladribine exposure of 25%.
Clinical experience in patients with moderate to severe renal impairment (i.e., CLCRbelow 60 mL per minute) is limited [see Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
No clinically significant differences in cladribine pharmacokinetics were observed when usedconcomitantly with pantoprazole or interferon beta-1a.
In Vitro Studies
It has been reported that lamivudine can inhibit the phosphorylation of cladribine intracellularly.
Potential competition for intracellular phosphorylation exists between cladribine and compoundsthat require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine,ribavirin, stavudine, and zidovudine).
Cytochrome P450 (CYP) Enzymes: Cladribine is not a substrate of cytochrome P450 enzymesand does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8,CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Cladribine has no clinically meaningfulinductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.
Transporter Systems: Cladribine is a substrate of P-glycoprotein (P-gp), breast cancer resistanceprotein (BCRP), equilibrative nucleoside transporter 1 (ENT1) and concentrative nucleosidetransporter 3 (CNT3). Inhibition of BCRP in the gastrointestinal tract may increase the oralbioavailability and systemic exposure of cladribine. Intracellular distribu |
