The volume of distribution is large, indicating extensive tissue distribution and intracellular uptake. Studies revealed a mean volume of distribution of cladribine in the range of 480 to 490 L. The plasma protein binding of cladribine is 20%, and independent of plasma concentration.
The distribution of cladribine across biological membranes is facilitated by various transport proteins, including ENT1, CNT3 and BCRP.
In vitro studies indicate that cladribine efflux is only minimally P-gp related. Clinically relevant interactions with inhibitors of P-gp are not expected. The potential consequences of P-gp induction on the bioavailability of cladribine have not been formally studied.
In vitro studies showed negligible transporter-mediated uptake of cladribine into human hepatocytes.
Cladribine has the potential to penetrate the blood brain barrier. A small study in cancer patients has shown a cerebrospinal fluid/plasma concentration ratio of approximately 0.25.
Cladribine and/or its phosphorylated metabolites are substantially accumulated and retained in human lymphocytes. In vitro, intra- versus extracellular accumulation ratios were found to be around 30 to 40 already 1 hour after cladribine exposure.
Biotransformation
The metabolism of cladribine was studied in MS patients following the administration of a single 10-mg tablet and a single 3-mg intravenous dose. Following both oral and intravenous administration, the parent compound cladribine was the main component present in plasma and urine. The metabolite 2-chloroadenine was a minor metabolite both in plasma and in urine, e.g. accounting only for ≤3% of plasma parent drug exposure after oral administration. Only traces of other metabolites could be found in plasma and in urine.
In hepatic in vitro systems, negligible metabolism of cladribine was observed (at least 90% was unchanged cladribine).
Cladribine is not a relevant substrate to cytochrome P450 enzymes and does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Inhibition of these enzymes or genetic polymorphisms (e.g. CYP2D6, CYP2C9 or CYP2C19) are not expected to result in clinically significant effects on cladribine pharmacokinetics or exposure. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.
After entering the target cells, cladribine is phosphorylated to cladribine monophosphate (Cd-AMP) by DCK (and also by deoxyguanosine kinase in the mitochondria). Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and cladribine triphosphate (Cd-ATP). The dephosphorylation and deactivation of Cd-AMP is catalysed by cytoplasmic 5'-NTase. In a study of the intracellular pharmacokinetics of Cd-AMP and Cd-ATP in patients with chronic myelogenous leukaemia, the levels of Cd-ATP were approximately half of the Cd-AMP levels.
Intracellular half-life of Cd-AMP was 15 h. Intracellular half-life of Cd-ATP was 10 h.
Eliminaion
Based on pooled population pharmacokinetic data from various studies, the median values for elimination were 22.2 L/h for renal clearance and 23.4 L/h for non-renal clearance. Renal clearance exceeded the glomerular filtration rate, indicating active renal tubular secretion of cladribine.
The non-renal part of the elimination of cladribine (approximately 50%) consists of negligible hepatic metabolism and of extensive intracellular distributio |
