n and trapping of the active cladribine principle (Cd-ATP) within the targeted intracellular compartment (i.e. the lymphocytes) and subsequent elimination of intracellular Cd-ATP according to the life-cycle and elimination pathways of these cells.
The estimated terminal half-life for a typical patient from the population pharmacokinetic analysis is approximately 1 day. This however does not result in any drug accumulation after once daily dosing as this half-life only accounts for a small portion of the AUC.
Dose and time dependence
After oral administration of cladribine across a dose range from 3 to 20 mg, Cmax and AUC increased in a dose-proportional fashion, suggesting that absorption is not affected by rate- or capacity-limited processes up to a 20 mg oral dose.
No significant accumulation of cladribine concentration in plasma has been observed after repeated dosing. There is no indication that cladribine pharmacokinetics might change in a time-dependent fashion after repeated administration.
Special populations
No studies have been conducted to eva luate the pharmacokinetics of cladribine in elderly or in paediatric MS patients, or in subjects with renal or hepatic impairment.
A population kinetic analysis did not show any effect of age (range 18 to 65 years) or gender on cladribine pharmacokinetics.
Renal impairment
Renal clearance of cladribine was shown to be dependent on creatinine clearance. Based on a population pharmacokinetic analysis including patients with normal renal function and with mild renal impairment, total clearance in patients with mild renal impairment (CLCR = 60 mL/min) is expected to decrease moderately, leading to an increase in exposure of 25%.
Hepatic impairment
The role of hepatic function for the elimination of cladribine is considered negligible.
Pharmacokinetic interactions
A drug interaction study in MS patients showed that the bioavailability of 10 mg oral cladribine was not altered when co-administered with pantoprazole.
5.3 Preclinical safety data
Non-clinical safety pharmacological and toxicological assessment of cladribine in animal models relevant for the safety assessment of cladribine did not yield significant findings other than those predicted by the pharmacologic mechanism of cladribine. The primary target organs identified in the repeat-dose toxicology studies by parenteral routes (intravenous or subcutaneous) up to 1-year duration in mice and monkeys were the lymphoid and haematopoietic system. Other target organs after longer administration (14 cycles) of cladribine to monkeys by subcutaneous route were the kidneys (karyomegaly of renal tubular epithelium), adrenals (cortex atrophy and decreased vacuolation), gastrointestinal tract (mucosa atrophy) and testes. Effects on the kidneys were also seen in mice.
Mutagenicity
Cladribine is incorporated into DNA strands and inhibits DNA synthesis and repair. Cladribine did not induce gene mutation in bacteria or mammalian cells, but it was clastogenic causing chromosomal damage in mammalian cells in vitro at a concentration which was 17-fold above the expected clinical Cmax. In vivo clastogenicity in mice was detected at 10 mg/kg, which was the lowest dose tested.
Carcinogenicity
The carcinogenic potential of cladribine was assessed in a long-term 22-month study with subcutaneous administration in mice and in a short-term 26-week study by oral route in transgenic mice.
• In the long-term carcinogenicity |
