The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis

Abstract

Cladribine Tablets (MAVENCLAD®) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.

Conflict of interest statement

Robert Hermann served as an external clinical pharmacology expert advisor for various aspects of several cladribine studies, and received financial support for research, consulting and training services from Merck KGaA, Darmstadt, Germany. Mats Karlsson is an employee of Uppsala University, which has performed contractual research for Merck KGaA, Darmstadt, Germany. Ana Novakovic and Markus Fluck are employees of Merck KGaA, Darmstadt, Germany, and Nadia Terranova and Alain Munafo are employees of Merck Serono SA, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.

Figures

Fig. 1

Mean (standard deviation) plasma cladribine concentration by treatment. IV intravenous. Adapted from Munafo et al. [21]

Fig. 2

Population pharmacokinetic visual predictive checks for plasma cladribine concentrations in fasted and fed conditions. Light blue shaded area indicates simulated median with uncertainty; pink shaded area indicates simulated 5th and 95th percentiles with uncertainty; solid blue line indicates observed median; dashed blue line indicates observed 5th and 95th percentiles. Adapted from Savic et al. [19]. © The Authors 2017

Fig. 3

Measured cladribine plasma concentration by visit: a 3.5 mg/kg dose group; b 5.25 mg/kg dose group (pharmacokinetic population). D day, W week

Fig. 4

Cladribine plasma concentration versus ΔΔQTcF using visit baseline (ECG population of the CLARITY study). Placebo-adjusted difference of QTcF to visit baseline and cladribine concentrations, including regression line: number of subjects = 93; number of non-missing observations = 434; intercept = − 0.09, slope + 6.30E−06; p value = 0.761. ECG electrocardiogram

Fig. 5

Model-derived exposure–effect relationship, together with the range of cladribine effect compartment exposure at the end of year 2 of the CLARITY study. The black line represents the model-derived relationship between cladribine exposure in the effect compartment (x-axis) and the effect (y-axis), which is the drug-dependent factor multiplying the underlying hazard of having a relapse that exists in the absence of treatment. The grey line represents the Emax, estimated at 72%. The 5th–95th range of effect compartment exposure at the end of year 2 (based on subjects in the CLARITY trial) following the 3.5 mg/kg (blue line) and 5.25 mg/kg (green line) regimens is also shown, with the black dots representing the respective median exposure. Emax maximum obtainable effect

Fig. 6

Predictions of 4-year hazard and survival for experiencing a first relapse in patients with 1 relapse in the previous 12 months, together with predictions of 4-year EDSS time-course for the typical subject. The lines represent predictions from the model for a the hazard, b survival (fraction relapse-free patients), and c EDSS progression over 4 years following treatment according to five treatment sequences: (1) 4 years of placebo (red); (2) 4 years of Cladribine Tablets, 7 mg/kg cumulative dose (brown dashes); (3) 2 years of Cladribine Tablets followed by 2 years of placebo, 3.5 mg/kg cumulative dose—represents the recommended treatment sequence (green); (4) 2 years of placebo followed by 2 years of Cladribine Tablets, 3.5 mg/kg cumulative dose (blue dashes); and (5) 2 years of Cladribine Tablets followed by 2 years of placebo, 5.25 mg/kg cumulative dose (purple). EDSS Expanded Disability Status Scale. Adapted from Novakovic et al. [39]. © The American College of Clinical Pharmacology 2018

Fig. 7

Repeated time-to-event model predictions of relapse risk for the typical patient (weight = 69.3 kg; creatinine clearance = 104.5 mL/min; number of relapses in the 12 months preceding study entry = 1) treated without postponement and with postponements of different month blocks (from 1 month, up to 9 months) during year 2. Adapted from Terranova et al. [42]. © The Authors 2018