nate cladribine to a significant extent.
11 DESCRIPTION
MAVENCLAD contains the nucleoside metabolic inhibitor cladribine, which is a white oralmost white, non-hydroscopic, crystalline powder with the molecular formula C10H12ClN5O3and molecular weight 285.69. It differs in structure from the naturally occurring nucleoside,deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring.
The chemical name of cladribine is 2-chloro-2′-deoxy-adenosine. The structural formula isshown below:
Cladribine is stable at slightly basic and at neutral pH. The main degradation pathway ishydrolysis and at acidic pH significant decomposition occurs with time. The ionization behaviorof the molecule over the pH range 0 to 12 is characterized by a single pKa of approximately1.21.
MAVENCLAD is provided as 10 mg tablets for oral use. Each MAVENCLAD 10 mg tabletcontains cladribine as an active ingredient and hydroxypropyl betadex, magnesium stearate, andsorbitol as inactive ingredients.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which cladribine exerts its therapeutic effects in patients with multiplesclerosis has not been fully elucidated but is thought to involve cytotoxic effects on B andT lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.
12.2 Pharmacodynamics
MAVENCLAD causes a dose-dependent reduction in lymphocyte count. The lowest absolutelymphocyte counts occurred approximately 2 to 3 months after the start of each treatment cycleand were lower with each additional treatment cycle. At the end of Year 2, 2% of patientscontinued to have absolute lymphocyte counts less than 500 cells per microliter. The mediantime to recovery from lymphocyte counts less than 500 cells per microliter to at least 800 cellsper microliter was approximately 28 weeks [see Warnings and Precautions (5.3)].
12.3 Pharmacokinetics
Cladribine is a prodrug that becomes active upon phosphorylation to its 2-chlorodeoxyadenosinetriphosphate (Cd-ATP) metabolite.
The pharmacokinetic parameters presented below were assessed following oral administration ofcladribine 10 mg, unless otherwise specified. The cladribine mean maximum concentration(Cmax) was in the range of 22 to 29 ng/ mL and corresponding mean AUC was in the range of 80to 101 ng•h/mL.
The Cmax and AUC of cladribine increased proportionally across a dose range from 3 to 20 mg.
No accumulation of cladribine concentration in plasma was observed after repeated dosing.
Absorption
The bioavailability of cladribine was approximately 40%. Following fasted administration ofcladribine, the median time to maximum concentration (Tmax) was 0.5 h (range 0.5 to 1.5 hours).
Effect of Food
Following administration of cladribine with a high fat meal, the geometric mean Cmax decreasedby 29% and AUC was unchanged. The Tmax was prolonged to 1.5 hours (range 1 to 3 hours).
Thisdifference is not expected to be clinically significant.
Distribution
Cladribine mean apparent volume of distribution ranges from 480 to 490 liters. The plasmaprotein binding of cladribine is 20% and is independent of concentration, in vitro.
Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes wereapproximately 30 to 40 times extracellular, in vitro.
Cladribine has the potential to penetrate the blood brain barrier. A cerebrospinal fluid/plasmaconcentration ratio of approxima |
