Clinical Pharmacokinetics (2019) 58:283–297
`https://doi.org/10.1007/s40262-018-0695-9
`
`REVIEW ARTICLE
`
`The Clinical Pharmacology of Cladribine Tablets for the Treatment
`of Relapsing Multiple Sclerosis
`
`Robert Hermann1 · Mats O. Karlsson2 · Ana M. Novakovic3 · Nadia Terranova4 · Markus Fluck3 · Alain Munafo4
`
`Published online: 10 July 2018
`© The Author(s) 2018
`
`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 pharma-
`cology 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 (T
`max) of 0.5 h (range 0.5–1.5 h) in fasted patients.
`When administered with food, absorption is delayed (median T
`max 1.5 h, range 1–3 h), and maximum concentration (C
`max)
`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.
`
` * Robert Hermann
`robert.hermann@cr-appliance.com
`
`1 Clinical Research Appliance (Cr Appliance),
`Heinrich-Vingerhut-Weg 3, 63571 Gelnhausen, Germany
`
`2 Department of Pharmaceutical Biosciences, Uppsala
`University, Uppsala, Sweden
`
`3 Merck KGaA, Darmstadt, Germany
`
`4 Merck Institute for Pharmacometrics, Merck Serono S.A.,
`Switzerland, an Affiliate of Merck KGaA, Darmstadt,
`Germany
`
`Key Points
`
`This review discusses the clinical pharmacology of Clad-
`ribine Tablets in patients with relapsing multiple sclero-
`sis, presenting pharmacokinetic, pharmacodynamic and
`pharmacometric data.
`
`Cladribine Tablets are associated with a selective reduc-
`tion in lymphocyte counts and durable efficacy relative
`to the fast disposition in plasma, and short-term treat-
`ment posology in each of the 2 treatment years.
`
`The recommended cumulative dose of Cladribine Tab-
`lets 3.5 mg/kg over 2 years is shown to be appropriate in
`reducing relapse risk.
`
`Vol.:(0123456789)
`
`Hopewell EX1079
`Hopewell v. Merck
`IPR2023-00481
`
`1
`
`

`

`284
`
`1 Introduction
`
`Multiple sclerosis (MS) is a neurodegenerative disease,
`where a patient’s immune system attacks their central
`nervous system, resulting in demyelination, axonal dam-
`age and progressive disability [1, 2]. Cladribine Tablets
` (MAVENCLAD®; Merck Serono Europe Ltd), an oral
`formulation of cladribine, were shown to have significant
`efficacy for the treatment of relapsing MS in placebo-
`controlled, phase III trials [3–5]. A cumulative dose of 3.5
`mg/kg body weight (consisting of 2 annual courses that are
`each comprised of 2 treatment weeks; 1 at the start of the
`first month and 1 at the start of second month of each year)
`has been approved for the treatment of adults with certain
`types of relapsing MS [6–8]. The short-term treatment
`posology of Cladribine Tablets has the potential to facilitate
`patient adherence [4], which is an ongoing challenge for the
`long-term treatment of MS [9].
`Cladribine is a nucleoside analogue of deoxyadenosine.
`The cladribine prodrug is phosphorylated intracellularly to
`its active product, 2-chlorodeoxyadenosine triphosphate
`(Cd-ATP), by deoxycytidine kinase. This deoxynucleotide
`product is degraded in most cells, by 5(cid:1929)-nucleotidase. Cells
`such as lymphocytes that contain a high deoxycytidine
`kinase activity but low 5(cid:1929)-nucleotidase activity, i.e. a high
`deoxycytidine kinase to 5(cid:1929)-nucleotidase activity ratio, accu-
`mulate deoxynucleotides to toxic concentrations, resulting
`in lymphocyte cell death. By this mechanism, Cladribine
`Tablets exert a selective mode of action on B and T lym-
`phocytes [10, 11]. Variations in the expression levels of
`deoxycytidine kinase and 5(cid:1929)-nucleotidase between immune
`cell subtypes explain differences in immune cell sensitivity
`to cladribine. Because of these expression levels, cells of
`the innate immune system are less affected than cells of the
`adaptive immune system [12, 13]. Cladribine Tablets have
`been described as a selective immune reconstitution therapy
`
`R. Hermann et al.
`
`due to their selective effect on the adaptive versus innate
`immune system, together with the short and intermittent
`nature of the treatment courses [14, 15]. The current theory
`is that by inducing lymphopenia, Cladribine Tablets reset
`the immune system [15].
`Cladribine was first established as a parenteral formula-
`tion for the treatment of B- and T cell lymphoid malignan-
`cies, including hairy cell leukaemia and chronic lymphocytic
`leukaemia [16, 17]. The clinical pharmacokinetics (PK) of
`parenteral cladribine in patients with malignancies were pre-
`viously reported by Liliemark in 1997 [18], reflecting the
`state of knowledge at that time. Due to the recent approval
`of Cladribine Tablets, a decision that was based on a sub-
`stantial amount of new study data, an up-to-date review of
`the clinical pharmacology of cladribine is warranted [3, 19,
`20]. Here, we review the clinical PK and outcomes of phar-
`macometric analyses (PK and primary pharmacodynamics
`[PD]) of the oral tablet formulation of cladribine in patients
`with MS in order to provide a comprehensive and timely
`summary of the available data. This report represents a nar-
`rative review of data from publications, congress materials,
`label information, and unpublished data on file.
`
`2 Pharmacokinetics (PK)
`
`2.1 Overview of Studies
`
`The PK of Cladribine Tablets has been investigated in 5
`phase I studies in patients with MS, plus a subpopulation
`of the phase III CLARITY clinical trial. A summary of the
`phase I studies is presented in Table 1. In addition, data from
`3 of the PK studies (studies 25803, 26127 and 26486) plus
`the PK subpopulation from the CLARITY clinical trial (see
`footnote in Table 2) were recently combined in a population
`PK analysis [19]. The population PK analysis was performed
`
`Table 1 Phase I pharmacokinetics studies of Cladribine Tablets
`
`Study number
`
`Study description
`
`Num-
`ber of
`patients
`
`Cladribine dose and administration
`method
`
`Included in popula-
`tion pharmacokinetic
`analysis?
`
`References
`
`IXR-102-09-186 Absolute bioavailability study
`
`26
`
`25803
`
`26127
`
`26486
`
`27967
`
`Bioavailability and metabolite study 16
`
`Food interaction study (high-fat
`breakfast)
`
`Drug interaction study (interferon-
`β1a)
`
`Study to assess interactions with
`pantoprazole
`
`16
`
`16
`
`18
`
`3 mg intravenous/3 and 10 mg
`single oral tablets
`
`3 mg intravenous/10 mg single oral
`tablet
`
`10 mg single oral tablet
`
`1.75 mg/kg cumulative dose of oral
`tablets over 8 weeks
`
`10 mg single oral tablet
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`[21]
`
`[19]
`
`[19]
`
`[19]
`
`[19]
`
`2
`
`

`

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`285
`
`Table 2 Phase III clinical trials of Cladribine Tablets
`
`Trial name
`
`Study description
`
`A safety and efficacy study of oral clad-
`ribine in subjects with relapsing–remit-
`ting multiple sclerosis (CLARITY)
`
`CLARITY extension
`
`Randomised, double-blind, 3-arm,
`placebo-controlled, multicentre study
`to evaluate the safety and efficacy of
`oral cladribine in subjects with relaps-
`ing–remitting multiple sclerosis
`
`Double-blind, placebo-controlled, mul-
`ticentre, parallel group, extension trial
`to evaluate the safety and tolerability of
`oral cladribine in subjects with relaps-
`ing–remitting multiple sclerosis who
`have completed the CLARITY trial
`
`Oral cladribine in early multiple sclerosis
`(ORACLE-MS)
`
`Randomised, double-blind, clinical trial
`to assess the safety and efficacy of 2
`doses of Cladribine Tablets versus pla-
`cebo in patients who had a first clinical
`demyelinating event (clinically isolated
`syndrome)
`CT 3.5 Cladribine Tablets 3.5 mg/kg cumulative dose over 2 years, CT 5.25 Cladribine Tablets 5.25 mg/kg cumulative dose over 2 years, PBO
`placebo
`a Treatment arms in the CLARITY Extension study are shown as the CLARITY treatment on the left side of the arrow and the CLARITY Exten-
`sion treatment on the right side of the arrow
`b A subpopulation of 125 patients from the CT 3.5 and CT 5.25 treatment groups in the CLARITY study provided samples for pharmacokinetics
`analyses, including the population pharmacokinetic analysis by Savic et al. [19]
`
`Patients and treatment armsa ClinicalTrials.
`gov identifier
`
`References
`
`CT 3.5, n = 433b
`CT 5.25, n = 456b
`PBO, n = 437
`
`CT 3.5 (cid:314) PBO, n = 98
`CT 5.25 (cid:314) PBO, n = 92
`CT 3.5 (cid:314) CT 3.5, n = 186
`CT 5.25 (cid:314) CT 3.5, n = 186
`PBO (cid:314) CT 3.5, n = 244
`
`NCT00213135 [3]
`
`NCT00641537 [4]
`
`CT 3.5, n = 206
`CT 5.25, n = 204
`PBO, n = 206
`
`NCT00725985 [5]
`
`to characterise the concentration–time course of cladribine,
`to estimate interindividual variability in PK, and to identify
`covariates that explain such variability.
`
`2.2 Absorption
`
`Cladribine is rapidly absorbed after tablet administration
`(Fig. 1); oral administration of a single 10 mg tablet in a
`fasted state is associated with a median time to reach maxi-
`mum concentration (T
`max) of approximately 0.5 h (range
`0.5–1.5 h) [21]. The mean maximum concentration (C
`max)
`is in the range of 22–29 ng/mL, with the corresponding
`mean area under the concentration–time curve (AUC) in
`the range of 80–101 ng·h/mL (arithmetic means from vari-
`ous studies) [22]. Cladribine can be considered a Biop-
`harmaceutics Classification System (BCS) class III com-
`pound (low permeability, high solubility) [20]. The oral
`bioavailability of Cladribine Tablets when administered in
`the fasted state is approximately 40% [22], possibly lim-
`ited by breast cancer resistance protein (BCRP)-mediated
`intestinal efflux. In the phase III studies, patients were
`instructed to take their tablets after an overnight fast on
`an empty stomach, and, once administered, to wait at least
`1 h before eating. If a dose was to be administered in the
`afternoon, or if a subject had mistakenly eaten before dos-
`ing, subjects were to wait at least 4 h after eating their last
`meal before dosing. In a phase I study, it was shown that
`
`taking a single 10 mg Cladribine Tablet after a high-fat
`breakfast results in a delay of the median T
`max from 0.5 h
`in the fasted state to 1.5 h (range 1–3 h) in the fed state
`[22]. This is associated with a 29% reduction in the maxi-
`mum exposure of cladribine (geometric mean C
`max) com-
`pared with administration after an overnight fast, while
`the total exposure (estimated by noncompartment analysis)
`is minimally affected (geometric mean AUC from time
`zero to infinity (AUC ∞) was 72.8  ng·h/mL for the fed
`state versus 75.7 ng·h/mL for the fasted state). Cladrib-
`ine Tablets can therefore be administered without regard
`to food [22]. In the population PK analysis, absorption
`in the fasted state was described by a first-order process,
`and a transit-compartment model described the absorp-
`tion delay in the data from the fed state. The fed/fasted
`status of phase III subjects was classified as ‘unknown’
`for modelling purposes. For phase III subjects, the rate of
`absorption and bioavailability estimates were the same or
`very similar to the values for fed subjects, and absorption
`delay was more similar to the estimated value for fasted
`subjects. Oral bioavailability of Cladribine Tablets was
`estimated to be 45.6%, and coadministration with a high-
`fat meal resulted in a modest change in bioavailability to
`40.5%, and a modest delay in absorption (Fig. 2). This was
`not expected to have a clinically meaningful impact [19].
`Taken together, the noncompartmental and population PK
`
`3
`
`

`

`R. Hermann et al.
`
`286
`
`Fig. 1 Mean (standard
`deviation) plasma cladribine
`concentration by treatment.
`IV intravenous. Adapted from
`Munafo et al. [21]
`
`Fig. 2 Population pharma-
`cokinetic 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 uncer-
`tainty; solid blue line indicates
`observed median; dashed blue
`line indicates observed 5th and
`95th percentiles. Adapted from
`Savic et al. [19]. © The Authors
`2017
`
`analyses of cladribine bioavailability, rate of absorption,
`and food effects yielded consistent results.
`
`2.3 Distribution
`
`The volume of distribution of cladribine is large, in the range
`of 480–490 L, which indicates extensive tissue distribution
`
`and intracellular uptake [19, 22]. Various transporter pro-
`teins facilitate the distribution of cladribine across biological
`membranes, including equilibrative nucleoside transporter
`(ENT) 1, concentrative nucleoside transporter (CNT) 3 and
`BCRP. Cladribine is most likely transported into lympho-
`cytes by ENT1 and CNT3 [23, 24]. The ENT1 transporter
`protein is also thought to be an important contributor to
`
`4
`
`

`

`Clinical Pharmacology of Cladribine Tablets in Relapsing Multiple Sclerosis
`
`287
`
`the active efflux of cladribine from white blood cells [25].
`The oral bioavailability of cladribine may be limited by the
`efflux transporter BCRP, which has an affinity with clad-
`ribine (BCRP overexpression has been shown to strongly
`reduce the rate of 2-CdA accumulation in human osteosar-
`coma cells) [26] and is expressed at high levels in the small
`intestine [27]. The contribution of P-glycoprotein (P-gp;
`ABCB1) to cladribine efflux is probably not important for
`the overall bioavailability of Cladribine Tablets, based on
`results of studies in MDCKII-MDR1 cells that show P-gp is
`not an efficient transporter of cladribine [22, 28]. Clinically
`relevant interactions with inhibitors of P-gp are therefore
`not expected.
`Results of an uptake study of 14C-labelled cladribine into
`cryopreserved human hepatocytes suggest that transporter-
`mediated uptake of cladribine into human hepatocytes is
`negligible (data on file). Cladribine and/or its phosphoryl-
`ated metabolites are substantially accumulated and retained
`in human lymphocytes. As shown in vitro, cladribine is rap-
`idly distributed to, and retained in (either as parent drug or
`its phosphorylated metabolites), human lymphocytes, result-
`ing in approximately 30- to 40-fold intracellular accumula-
`tion compared with extracellular concentrations, as early as
`1 h after cladribine exposure (data on file). Cladribine has
`the potential to penetrate the blood–brain barrier [18]. A
`small study in another indication has shown a cerebrospi-
`nal fluid/plasma concentration ratio of approximately 0.25
`[29]. In spiked human plasma, the plasma protein binding of
`cladribine was 20%, and independent of plasma cladribine
`concentration (data on file).
`
`2.4 Metabolism
`
`Cladribine metabolism was investigated in patients with MS
`following the administration of a single 10 mg tablet and a
`single 3 mg intravenous dose (study 25803) (Table 1). Fol-
`lowing 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, i.e. amounting
`to ≤ 3% of the AUC of parent compound in plasma after oral
`administration. Only traces of other metabolites could be
`found in plasma and urine [30]. In hepatic in vitro systems,
`cladribine was only metabolised to a very low extent, with at
`least 90% of radiolabelled cladribine remaining unchanged
`(data on file).
`Cladribine is not a relevant substrate to cytochrome
`P450 (CYP) enzymes, based on reaction phenotyping stud-
`ies where cladribine was incubated with microsomes pre-
`pared from human recombinant lymphoblastoid cells that
`were genetically engineered to express specific human CYP
`enzymes that may be responsible for the metabolism of
`
`cladribine in vitro: CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1,
`and 3A4 (data on file).
`After entering the target cells, cladribine is phosphoryl-
`ated to cladribine monophosphate (Cd-AMP) by deoxycy-
`tidine kinase (and also by deoxyguanosine kinase in the
`mitochondria). Cd-AMP is further phosphorylated to chlo-
`rodeoxyadenosine diphosphate (Cd-ADP), and Cd-ADP is in
`turn phosphorylated by 5(cid:1929)-nucleotidase to Cd-ATP [10, 11].
`In a study of the intracellular PK of Cd-AMP and Cd-ATP in
`another indication, the levels of Cd-ATP were approximately
`half that of the Cd-AMP levels. The intracellular half-life of
`Cd-AMP was 15 h and the intracellular half-life of Cd-ATP
`was 10 h [31].
`
`2.5 Elimination
`
`The population PK analysis showed that renal and non-renal
`routes of cladribine elimination are of approximately equal
`importance; the median values were estimated to be 22.2
`L/h for renal clearance and 23.4 L/h for non-renal clear-
`ance. Renal clearance correlated with creatinine clearance
` (CLCR), and CLCR was therefore used to predict renal clad-
`ribine clearance in patients with renal impairment using the
`population PK model, with the assumption that changes in
` CLCR only affect the renal component of total cladribine
`clearance. Intersubject variability for non-renal clearance
`was estimated to be 7.6%. The nonrenal proportion of clad-
`ribine clearance (approximately 50%) comprises negligible
`hepatic metabolism with extensive intracellular distribution
`and trapping of Cd-ATP within lymphocytes, and the sub-
`sequent elimination of intracellular Cd-ATP according to
`lymphocyte elimination pathways and lifecycle [22].
`Renal clearance appears to exceed glomerular filtration
`rate, indicating net tubular excretion in addition to glomeru-
`lar filtration [19]. As cladribine was shown not to be a sub-
`strate of the kidney-specific basolateral transporters OCT2,
`OAT1, and OAT3, nor of the kidney-specific apical trans-
`porter OAT4 (data on file), only BCRP [26, 28], ENT1/2 and
`CNT2/3 [32] remain as conceivable candidate transporters
`for active tubular secretion of cladribine. Basolateral-located
`ENT1 is the most likely candidate to facilitate basolateral
`uptake of cladribine as none of the other basolateral can-
`didates tested actually facilitated cladribine uptake. In the
`apical membrane of renal tubular cells, of the 3 transport-
`ers implicated in renal transport of cladribine, only BCRP
`has been unambiguously shown to transport cladribine
`efficiently in multiple expression systems. P-gp-mediated
`transport does not seem to be efficient, and, for MRP4,
`transport was not shown in either of the test systems studied
`(HEK293-MRP4, MDCKII-MRP4; data on file). Based on
`these findings, the apical efflux is likely driven by BCRP,
`with some contribution of ENT1.
`
`5
`
`

`

`288
`
`R. Hermann et al.
`
`A decline in total cladribine clearance by 21% is pre-
`dicted for patients with a CLCR of 60 mL/min (lower bound
`of mild renal impairment range), by 30% in patients with a
` CLCR of 40 mL/min (moderate renal impairment), and by
`40% in patients with a CLCR of 20 mL/min (severe renal
`impairment), when compared with patients with normal
`renal function. As a result, an increase in AUC of 25, 45 and
`65% is to be expected for an otherwise typical patient with
`mild, moderate, and severe renal impairment, respectively.
`There is good confidence in the predicted clearance value for
`patients with mild renal impairment since the clinical stud-
`ies included a substantial proportion of patients (25%) with
`mild impairment (CLCR of ≥ 60 to < 90 mL/min). In contrast,
`calculations for moderate and severe renal impairment suf-
`fer from more uncertainty, given the low number of patients
`with moderate or severe renal impairment in the population
`PK analysis (Table 3) [19, 20, 22].
`
`2.6 Dose and Time Dependency of PK
`
`C
`max and AUC increased in a dose-proportional fashion after
`oral administration of Cladribine Tablets across a range of
`doses from 3 to 20 mg, suggesting that absorption is not
`affected by rate- or capacity-limited processes up to a 20 mg
`oral dose [21, 22]. No significant accumulation of cladribine
`concentration in plasma after once-daily repeated dosing has
`been observed [22, 33]. There is no indication that cladribine
`PK might be time-dependent after repeated administration
`of Cladribine Tablets. PK were observed in both the mid-
`term (measurements at weeks 5, 9 and 13) and the long-term
`(measurements at weeks 48 and 52) in the CLARITY study
`[3]. There were very similar distributions of the observa-
`tions between visits, and no apparent trend in terms of either
`monotonic increases or decreases of cladribine concentra-
`tions with time (Fig. 3).
`
`2.7 Influence of Intrinsic Factors on PK
`
`Due to the long-lasting effects on lymphocytes, PK studies
`have only been conducted in patients with MS, therefore
`
`Table 3 Demographics of patients included in the population phar-
`macokinetic analysis
`
`Variable
`
`Age, years [median (range)]
`
`Body weight, kg [median (range)]
`Sex [n (%)]
` Male
`
` Female
`
`N = 173
`
`40 (19–65)
`
`69.2 (48.5–116.1)
`
`59 (34.1)
`
`114 (65.9)
`
`Creatinine clearance, mL/min [median (range)]
`
`107.9 (49.6–244.4)
`
`Adapted from Savic et al. [19]
`
`studies in special populations (including children or elderly
`patients, or patients with hepatic impairment) have not been
`performed. However, the influence of demographic covari-
`ates on PK parameters was studied as part of the population
`PK analysis. This did not show any effect of age (studies in
`patients aged 19–65 years) or sex on the PK of Cladribine
`Tablets beyond what is accounted for by the effect of CLCR
`on renal clearance [19]. As safety and efficacy in patients
`with moderate or severe renal impairment have not been
`established, Cladribine Tablets should not be used in such
`patients.
`No studies have been conducted in patients with hepatic
`impairment, therefore, the use of Cladribine Tablets is not
`recommended in patients with moderate or severe hepatic
`impairment (Child–Pugh score > 6) due to a lack of data
`[22].
`
`2.8 Drug Interactions
`
`Only a few clinically relevant drug interactions with Cladrib-
`ine Tablets are expected. The absence of drug–drug interac-
`tions with Cladribine Tablets is of particular benefit due to
`the high rates of comorbid conditions associated with MS
`[34], which are likely to require concomitant pharmaceuti-
`cal treatment.
`
`2.8.1 Pharmacodynamic (PD) Interactions
`
`There is a risk of mutual additive/synergistic effects on the
`immune system if Cladribine Tablets are used concomitantly
`with immunosuppressive or myelosuppressive therapies.
`Similarly, an additive effect on haematological adverse reac-
`tions is likely if Cladribine Tablets are used concomitantly
`with therapies that affect the haematological profile, such
`as carbamazepine [22]. Results from modelling analyses
`that examined the dose–exposure–response relationship
`with respect to absolute lymphocyte count (ALC) follow-
`ing administration of oral cladribine (see Sect. 4.1) dem-
`onstrated no statistically significant effect of concomitant
`glucocorticoids on the ALC response to cladribine [20].
`
`2.8.2 PK Interactions
`
`Cladribine as  a  Perpetrator Drug of  PK Interactions
`Cladribine Tablets contain hydroxypropyl betadex, and
`there is the potential for complex formation between free
`cyclodextrin, released from the Cladribine Tablets formula-
`tion, and other medicinal products [22]. Complex forma-
`tion potentially leads to an increase in bioavailability of the
`concomitantly administered product (especially medicinal
`products with poor solubility and low bioavailability). The
`risk of complex formation with cyclodextrin can be mini-
`mised by separating the administration of any other oral
`
`6
`
`

`

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`
`289
`
`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
`
`pharmaceutical from the administration of Cladribine Tab-
`lets by at least 3 h, during the limited number of days in a
`treatment year in which Cladribine Tablets are administered
`[22].
`The potential of cladribine to alter the PK of coad-
`ministered object drugs is considered low. With regard to
`metabolism-based drug interactions, cladribine does not
`show potential to act as an inhibitor of CYP1A2, CYP2B6,
`CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and
`CYP3A4, based on studies in pooled human liver micro-
`somes (data on file). Therefore, cladribine is unlikely to con-
`tribute to any inhibitory drug–drug interactions in vivo that
`are mediated by CYP450 enzymes. Cladribine appears to
`have no clinically meaningful inductive effect on CYP1A2,
`CYP2B6 and CYP3A4 enzymes, although the results from 2
`in vitro studies of pooled human liver microsomes were not
`entirely consistent and conclusive (data on file). There is suf-
`ficient in vitro information available to support the view that
`
`cladribine does not inhibit the most important ABC trans-
`porters in vivo, i.e. P-gp (ABCB1) [in Caco-2 cells], BCRP
`(ABCG2) [in MDCKII-BCRP cells], and MRP2 (ABCC2),
`MRP4 (ABCC4) and MRP5 (ABCC5) [in membrane vesi-
`cle preparations], nor any of the examined organic anion
`transporters, i.e. OATP1B1 and OATP1B3 (in transfected
`HEK cells), OAT1 and OAT3 (in membrane vesicle prepara-
`tions) and OAT4 (in vector-transfected S2 cells), and organic
`cation transporters, i.e. OCT1 (in transfected HEK cells)
`and OCT2 (in membrane vesicle preparations) [data on file]
`[20]. Data on inhibition of ENTs (ENT1 and ENT2), CNTs
`(CNT1, CNT2, CNT3), and MATE transporters by cladrib-
`ine are currently incomplete or lacking.
`
`Cladribine as  an  Object Drug of  PK Interactions
`A drug interaction study with pantoprazole has been con-
`ducted to investigate whether elevated gastric pH may alter
`the oral bioavailability of, and thus exposure to, Cladribine
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`R. Hermann et al.
`
`Tablets. Repeated single doses of oral pantoprazole 40 mg
`were administered 15 h and 3 h prior to administration of
`cladribine in patients with MS. The estimated geometric
`mean ratios of cladribine with pantoprazole versus cladrib-
`ine alone were near unity for all parameters (1.006 and 0.980
`for the primary endpoints AUC ∞ and C
`max, respectively).
`The 90% confidence intervals (CIs) of the geometric mean
`ratios were 0.907–1.116 for AUC ∞ and 0.804–1.194 for
`C
`max, both within the standard bioequivalence acceptance
`limits of 0.8–1.25. It was therefore concluded that coad-
`ministration of pantoprazole with Cladribine Tablets had no
`effect on the rate and extent of the absorption of cladribine
`[19].
`As cladribine is only marginally metabolised by CYP-
`based metabolism, inhibition of any of the major CYP
`enzymes or genetic polymorphisms thereof (e.g. CYP2D6,
`CYP2C9 or CYP2C19) are not expected to result in clini-
`cally significant effects on cladribine PK or exposure.
`Cladribine is a BCRP substrate (see Sect. 2.3), therefore
`BCRP inhibitors may have an effect on cladribine exposure.
`However, marketed BCRP inhibitors (including the tyros-
`ine kinase inhibitors imatinib, sunitinib and gefitinib) are
`altogether contraindicated in cladribine-treated patients,
`together with the older-generation antihypertensive drug
`reserpine, which has been discontinued from most markets,
`as well as the estrogen receptor antagonist tamoxifen.
`Based on the findings of a recent database search (Uni-
`versity of Washington Drug–Drug Interaction Database
`[35]), the susceptibility of cladribine to become a victim/
`object of transporter-based drug interactions is limited in
`clinical practice to a few marketed products with ENT1 or
`BCRP inhibitory capacity, which are not contraindicated
`for cladribine-treated patients. Coadministration of potent
`ENT1 or BCRP inhibitors may theoretically alter the oral
`absorption/bioavailability of Cladribine Tablets. To apply a
`conservative approach, coadministration of these products
`should be avoided during each 4- to 5-day treatment period
`of Cladribine Tablets [22].
`Cladribine may theoretically become the object/victim
`of potent CNT2 and CNT3 inhibitors. However, the data-
`base search was unable to identify any relevant marketed
`CNT2 inhibitors, only the cytotoxic nucleoside analogues
`fludarabine and clofarabine as potent CNT3 inhibitors,
`which are contraindicated in cladribine-treated patients.
`Identified ENT1 inhibitors include the P2Y12 antagonist
`ticagrelor, the adenosine reuptake inhibitors dipyridamole
`and dilazep, the dihydropyridine calcium channel block-
`ers nimodipine, nifedipine and nitrendipine, and the PDE3
`inhibitor cilostazol.
`It has been reported that lamivudine can inhibit the
`phosphorylation of cladribine intracellularly, and thereby
`the therapeutic efficacy of cladribine [36]. Therefore, com-
`pounds that require intracellular phosphorylation to become
`
`active, such as lamivudine, zalcitabine, ribavirin, stavudine,
`and zidovudine should not be administered concomitantly
`with cladribine. Since cladribine therapy must not be initi-
`ated in patients with acute or chronic infections, this group
`of antiviral and antiretroviral drugs will not be used in
`patients treated with Cladribine Tablets.
`The population PK analysis included 1 study on drug
`interactions with interferon-β1a, and no clinically relevant
`PK interaction was found [19, 22]. However, it should be
`noted that Cladribine Tablets are not intended for use with
`other disease-modifying drugs for MS as their safety and
`efficacy with concomitant treatment has not been established
`[22].
`
`2.8.3 Summary of Drug Interactions
`
`Due to the posology of Cladribine Tablets (and its relatively
`fast disposition), cladribine is only present in the body for a
`few days of every treatment year. This means that treatments
`that have the potential to influence the absorption of clad-
`ribine, e.g. inhibitors of transporters such as ENT1, CNT3
`and BCRP (e.g. eltrombopag, dilazep, nifedipine, nimodi-
`pine, cilostazol, sulindac or reserpine) may be taken safely/
`effectively outside of the treatment window for Cladribine
`Tablets. The absence of drug–drug interactions with Clad-
`ribine Tablets is of particular benefit due to the high rates
`of comorbid conditions associated with MS [34], which are
`likely to require concomitant pharmaceutical treatment.
`
`3 Cardiac Safety
`
`3.1 Preclinical Data
`
`Available nonclinical data do not suggest any clinically
`significant effects of cladribine on cardiac repolarisa-
`tion. In vitro, only a very high concentration of cladribine
` (10−4 M) resulted in a marginal inhibition (i.e. 13%) of the
`human ether-a-go-go-related gene (hERG) tail current.
`Based on this, the safety margin for IKr block of the high-
`est free cladribine concentration observed with Cladribine
`Tablets in humans is estimated to be 275-fold. In addi-
`tion, no effect on action potential duration, in particular on
`action potential duration at 90% repolarisation (APD90), was
`observed in isolated canine Purkinje fibres at cladribine con-
`centrations up to 10−4 M [20].
`Cladribine did not exert any effect on heart rate, mean,
`systolic or diastolic systemic arterial blood pressure or any
`electrocardiogram (ECG) outcomes in dogs. In particular,
`the duration of the heart rate-corrected QT intervals were
`
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`291
`
`not affected during an observation period of 4 h postdose.
`The cladribine exposure of animals exceeded the exposure
`