Clin. Pharmacokinet. 1997 Feb: 32 (2): 120-131
`DRUG DISPOSITION
`0312-5963/97/0002-0120/$06.00/0
`© Adis international Limited.All rights reserved.
`
`The Clinical Pharmacokinetics
`of Cladribine
`
`Jan Liliemark
`
`Department of Oncology, Karolinska Hospital, Stockholm, Sweden
`
`Contents
`
`SUMMATY 120
`1. Bioanalysis...ee 12]
`2. Bioavailability... 122
`2.1 Oral Administration .0ee 122
`2.2 Subcutaneous Administration... ee 123
`2.3 RectalAdministration .0... 123
`3. Distripution2ee 123
`3.1 Penetration of the Blood-Brain Barrier
`2oe 123
`4. Metabolism2.0 124
`Al Catabolism...
` e 124
`4.2 Bioactivation 2.0.ee 124
`4.3 Intracellular Pharmacokinetics 2.00.0 124
`4.4 Plasma/Cell Concentration Relationship .. 0.0... ee 125
`5. Pharmacodynamic Relationships2... 125
`6 Excretion 66.ee 127
`7.
`Interactionoe 127
`8. Interspecies Differences...1 128
`9. CONCIUSION2ee 129
`
`
`Summary
`
`Cladribine is a new purine nucleoside analogue with promising activity in
`low-grade lymphoproliferative disorders, childhood acute myelogenous leukae-
`mia and multiple sclerosis. Reversed phase high performance liquid chromatog-
`raphy and radioimmunoassay have been used for the analysis of the plasma
`pharmacokinetics of cladribine. The major (inactive) metabolite in plasma, chloro-
`adenine, can only be detected by liquid chromatography.
`The oral bioavailability of cladribine is 37 to 51%, and that of subcutaneous
`administration is 100%. The terminal half-life varies from 5.7 to 19.7 hours and
`the apparent volumeofdistribution from 54 to 357 L/m”. The concentration in
`the cerebrospinalfluid is 25% of that in plasmain patients without central nervous
`system disease; in patients with meningeal disease, the cladribine concentration
`in the cerebrospinal fluid exceeds that in plasma.
`Cladribine is a prodrug and needs intracellular phosphorylation to active
`nucelotides. The intracellular concentration of these metabolites is several hun-
`dred-fold higher than that of cladribine in plasmaandthey are retained in leukae-
`mia cells with half-lives between 9 and >30 hours depending on diagnosis and
`
`1
`
`Hopewell EX1048
`
`Hopewell EX1048
`
`1
`
`

`

`121
`Clinical Pharmacokinetics of Cladribine
`
`
`sampling schedule. There is no correlation between the plasma concentration of
`cladribine and that of the intracellular metabolites.
`The renal clearance of cladribine is 51% of total clearance and 21 to 35% of
`
`an intravenously administered dose is excreted unchanged in theurine. Pretreat-
`ment with cladribine increases the intracellular accumulation of the active me-
`tabolite of cytarabine, cytosine arabinoside 5’-triphosphate, by 36 to 40%.
`
`
`Thefirst report on the synthesis and antileukae-
`mic effect of cladribine (2-chloro-2’-deoxycytid-
`ine, CdA) was published in 1972.) Later it was
`discovered that severe immunodeficiencyin children
`was, in a fraction of patients, caused by deficient
`adenosine deaminase (ADA).”! Deoxyadenosine ac-
`cumulates in plasma and dATPin cells with high
`deoxycytidine kinase (dCK) activity. Such pertur-
`bations of the deoxyribonucleotide pools leads to
`DNA-strand breaks, poly(ADP)ribosyi transferase
`activation, consumption of NAD, ATP depletion
`and loss of viability.) Cladribine and other C-2
`halogenated purines(e.g. fludarabine)are resistant
`to ADA dueto protonation at N-7 instead of N-6"4!
`which prevents hydroxylation and deamination at
`N-6. Cladribine 5’-triphosphate, with similar toxic
`effects to those of dATP, accumulates in dCK-rich
`tissues; treatment with cladribine can, therefore,
`mimic ADA-deficiency.
`Due to the lack of a solid patent, the develop-
`ment of the drug for clinical use was severely
`slowed. Thanksto the efforts of Dennis Carson and
`Emmest Beutler at Scripps Clinic, La Jolla, cladrib-
`ine was eventually taken through preclinical and
`early clinical testing.>-7] Under the Orphan Drug
`Act, cladribine was licensed as Leustatin® in 1994
`and has emerged as one of the more important
`drugs in the therapeutic armamentagainst lympho-
`proliferative disorders.'®! The use of cladribine in
`children was investigated independently at St Jude
`Children’s Hospital, Memphis, USA.!°! While the
`metabolism and mechanism ofaction of cladribine
`waselucidated early, the clinical pharmacokinetics
`have not been delineated until recently. The phar-
`macokinetic data has, however, grownsteadily
`during recent years.
`Cladribineis the drug of choice for the treatment
`of hairy cell leukaemia.!!°'""! It has definite activity
`
`in chronic lymphocytic leukaemial!?-!5] and low-
`grade non-Hodgkin’s lymphoma!!>-!8] although the
`exact role of cladribine in the treatment of these
`diseases is still a matter of some controversy. The
`use of purine analogues in the treatment of low-
`grade lyphoproliferative disorders was recently re-
`viewed.!'9] Responses are also seen in acute my-
`elogenous leukaemiain children!©! and in psoriatic
`arthritis.2") A randomised, double-blind, cross-over
`trial showed impressive activity in patients with
`chronic progressive multiple sclerosis.!?2-23] In exper-
`imental systems, cladribine potentiates the immuno-
`suppressive effect of cyclosporin and has potential
`in the treatmentof transplant rejection.{74)
`
`1. Bioanalysis
`
`The plasma pharmacokinetics of cladribine
`have been studied during continuous infusion and
`after intravenous short infusion, subcutaneous in-
`jection,oral, and rectal administration. The concentra-
`tion of cladribine has been determined with liquid
`chromatography!*>6] and radioimmunoassay.!2027]
`Liquid chromatography has the advantage of iden-
`tifying the catabolite 2-chloroadenine (CAde)
`while radioimmunoassay can be somewhat more
`
`NH;
`
`ae
`
`SS
`
`cl
`
`N
`HOCH,
`
`oO
`
`N
`
`N
`
`OH
`
`Fig. 1. The chemical structure of cladribine (2-chloro-2’-
`deoxyadenosine).
`
`© Adis international Limited.All righis reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`2
`
`

`

`122
`Liliemark
`
`
`0.14 mg/kg
`0.28 mg/kg
`0.14 mg/kg
`
`© 10007intravenously orally
`
`subcutaneously
`5
`‘
`oaSo
`SEof 100
`o@
`S§
`£3ca
`ge
`8
`oO
`
`e
`
`10
`0
`
`0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`Time (h)
`
`Fig. 2. The plasma concentration of cladribine after intravenous [area under the concentration-time curve (AUC) = 791 nmol/L «
`hj, oral (AUC = 878 nmol/L * h), and subcutaneous (AUC = 709 nmol/L « h) administration of cladribine (from Liliemark et al.,8° with
`permission).
`
`sensitive (detection limit 1 vs 0.2 nmol/L). The
`comparison of pharmacokinetic data for cladribine
`betweeninvestigators is obscured by differences in
`the absorption coefficient (e= 15.0 x 103 L/mol)!!-28]
`used for determination of the cladribine concentra-
`tion in standards."! In the early clinical and phar-
`macokinetic studies (before 1993) the absorption
`coefficient for chloroadenine (€ = 12.6 x 10%
`L/mol) was used. Therefore, the dose and plasma
`concentration in these studies were overestimated
`by 15%.
`
`2. Bioavailability
`
`2.1 Oral Administration
`
`There are 4 reports on the oral bioavailability of
`cladribine.!?%-32] The oral bioavailability in these
`trials varies from 37 to 51% whenthe saline solu-
`tion for intravenous administration is given to pa-
`tients to drink.293932] Thus, when administered
`orally at about twice the intravenousdose,the areas
`underthe concentration-time curve (AUC)are sim-
`ilar (fig. 2).
`When compared with 2-hour intravenous infu-
`sion (0.12 mg/kg ~ 5 mg/m?) the maximum con-
`centration wasslightly higher but the peak briefer
`after oral (0.24 mg/kg ~ 10 mg/m?) or subcutane-
`ous administration (0.12 mg/kg) [142 nmol/Lafter
`intravenousinfusion vs 165 nmol/L after oral and
`and 268 nmol/L after subcutaneous administra-
`
`tion].°! In some other antimetabolites(i.e. cytara-
`bine and 6-mercaptopurine),!?334! bioactivation is
`impaired when the drug concentrations achieved
`are above the Michaelis-Menten constant (Km)
`of the bioactivating enzymes. The plasma concen-
`tration of cladribine achieved by subcutaneous or
`oral administration is, however, at least one log
`lower than the Km of dCK,the intracellular CdA phos-
`phorylation enzyme."°! Thus, the drug concentra-
`tions achieved with a standard dose are far from
`saturating the bioactivation.
`The interindividual variability of the bioavaila-
`bility is considerable [coefficient of variation (CV)
`= 28%] but the variability of the AUC after oral
`administration is not any greater than thatafter in-
`travenous administration (CV = 38 vs 36%),6°)
`Cladribine is not stable at low pH (pH < 2).
`However, attempts to increase the pH in the stom-
`ach with omeprazole before the oral administration
`of cladribine have not improvedthe bioavailability
`significantly.!?°! Neither was the use of enteric
`coated capsulesof any benefit.!3°! Concomitant food
`intake slowed and lowered the uptake of cladrib-
`ine.!?9] However, despite a limited bioavailability,
`oral administrationof cladribine has been used suc-
`cessfully in the treatment of previously untreated
`chronic lymphocytic leukaemia!3¢37) and psoriatic
`arthritis.{2)
`
`© Adis international Limited. Ail rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`3
`
`

`

`123
`Clinical Pharmacokinetics of Cladribine
`
`
`2.2 Subcutaneous Administration
`
`Cladribine has no local tissue toxicity and when
`given subcutaneously, the bioavailability is 100%.!20!
`Subcutaneously administered cladribine was used
`in 1 large trial on hairy ceil leukaemia. The thera-
`peutic results seems to be equivalent with those
`after continuous intravenous infusion.!'0!
`
`2.3 Rectal Administration
`
`Based on the impressive improvement of the
`bioavailability of 6-mercaptopurine with rectal
`administration as compared with oral administra-
`tion,8! an attempt has been madeto improvethe
`bioavailability of cladribine with rectal adminis-
`tration. However, cladribine is degraded by bacte-
`rial enzymes and the bioavailability by the rectal
`route is poor, only 20%.29)
`
`3. Distribution
`
`During continuousinfusion (5 to 10 mg/m? per
`24 hours which corresponds to a dose of 0.12 to
`0.24 mg/kg per 24 hours)!*0! the concentration of
`
`100
`
`(nmol/L) 5
`
` Plasmacladribine
`
`0
`
`6
`
`12
`
`ST
`18
`
`t
`24
`
`Time (h)
`Fig. 3. The mean plasma concentration of cladribine after 2
`hours intravenousinfusion in 12 patients. The dataarefitted to
`a 3-compartment open model. The horizontal line shows the
`steady-siate conceniration of cladribine in the same patients
`after continuous intravenous infusion of the same dose during
`24 hours. The broken lines represent 1 SD in the population
`(from Liliemark and Jutiusson,'4"! with permission).
`
`cladribine in plasma is 10 to 50 nmol/L,!6204))
`while during a 2-hour infusion of 5 mg/m?it is 100
`to 400 nmol/L!?741.421 (fig. 3). There appears to be
`a linear dose/concentration relationship for cladrib-
`ine in this dose range (0.2 mg/m?per hourto 2.5
`mg/m? per hour) although Markset al.!4?! reported
`a dose-dependent clearance decreasing from 52.7
`to 26.5 L/h/m?with increasing dosages from 3.5 to
`10.5 mg/m.
`The plasma elimination follows a 2- or 3-com-
`partment open model depending on sampling pro-
`cedure. The terminal half-life (t,) is relatively
`long, 7 to 19 hours. The pharmacokinetics of clad-
`ribine after intravenous administration are summar-
`ised in table I.
`
`3.1 Penetration of the Blood-Brain Barrier
`
`The concentration of cladribine in the cerebro-
`spinal fluid is approximately 25% of the plasma
`concentration at dose rates between 0.17 mg/m*/h
`and 2.5 mg/m*/h intravenously in patients without
`known meningeal disease.!*3-444¢] The kinetics of
`the cerebrospinal fluid concentration roughly fol-
`lowsthose ofthe plasma.'*7! The cerebrospinal fluid
`concentration increases linearly with dose.!*3-46]
`No data are available on the penetration of cladrib-
`ine into cerebral tissues. However, several responses
`have been noted in patients with astrocytomas,in-
`dicating that the drug is distributed to the brain,at
`least when the blood-brain barrier is damaged. Fur-
`thermore, cerebral toxicity was noted in patients
`treated with higher doses of cladribine (0.4 to 0.5
`mg/kg daily for 7 to 14 days) than commonly
`used, (271
`In 2 papers it has been reported that cladribine
`can indeed have an effect on meningeal disease
`when administered intravenously.!4748] In 1 patient,
`with a meningeal involvement of Waldenstrém’s
`macroglobulinaemia, the cerebrospinal fluid con-
`centration of cladribine exceeded that in plasma,
`which suggests that meningeal involvement in-
`creases the penetration of cladribine into the cere-
`brospinal fluid.(471
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet, 1997 Feb; 32 (2)
`
`4
`
`

`

`124
`Liliemark
`
`
`Table t. Plasma pharmacokinetics of cladribine
`Diagnosis
`n
`Dose/day Duration Mean AUC
`
`
`tya mean—typ ty Vdss mean Cl mean Reference
`
`(mg/m?)
`(h)
`(mol/L* h)
`(min)
`()) (SD) (lm?]
`(SD)
`(Un/m?]
`
`
`
`6.3
`9.9
`13.4
`14.2
`
`19.7
`5.7
`6.0
`
`368 (216)*
`53.6 (23.7)
`
`305.1
`
` 25.9(7.8)
`39.1 (6.8)
`36.1
`
`356.6 (225.2) 39.4 (12.4)
`121
`26.5-52.7°
`174
`46.1
`
`41
`43
`29
`20
`
`44
`45
`42
`
`CLL, HCL, and NHL
`CLL and NHL
`CLL
`Paediatric AML and ALL
`Paediatric AML
`Solid tumour
`CML
`
`12
`13
`4
`5
`25
`25
`1
`
`5.5
`5.0
`§0
`8.9
`8.9
`3.5-10.5
`6-12
`
`2
`2
`2
`24
`24
`2
`2
`
`0.59
`0.76
`0.70
`
`14
`0.7
`
`8
`
`3.1
`
`0.26-1.47
`0.53-1.14
`
`11.9
`
`1.5
`
`a_ Vd of the peripheral compartment.
`b Dose dependent.
`Abbreviations and symbols: ALL = acute tymphocytic leukaemia; AML = acute myelogenous leukaemia; AUC = area underthe concentration-
`time curve; Cl = clearance; CLL = chronic lymphocytic leukaemia; CML = chronic myelogenous leukaemia; h = hour(s); HCL = hairy cell
`leukaemia; NHL = non-Hodgkin’s lymphoma; n = numberof patients; tio = distribution half-life; ty4, = elimination half-life; ty, = terminal
`half-life; Vd = volume of distribution.
`
`4. Metabolism
`
`4.1 Catabolism
`
`CAdeis the major metabolite in plasma.!2>! The
`higher concentration of this catabolite in plasma
`after the oral administration of cladribine (fig. 4)is
`probably due to the degradation of cladribine by
`gastric acid and the subsequent absorption of the
`metabolite or by hepatic or intestinal first-pass ef-
`fect. CAde has no cytotoxic or antitumoureffectat
`the concentrations achieved.
`
`however, seemsto be phosphorylated readily to the
`monophosphate but,at least in vitro, the concentra-
`tions of the di- and triphosphate nucleotides are
`approximately 7 and 3 times lower than those of
`the monophosphate.!9°0!
`Cytoplasmatic 5’-nucleotidase!5!! dephosphoryl-
`ates and deactivates cladribine 5’-monophosphate.
`The level of this enzyme in tumourcells seems to
`be important for sensitivity to cladribine treat-
`ment!5!52] and probably determinesthe retention
`of cladribine nucleotides in tumourcells.
`
`4,2 Bioactivation
`
`4.3 Intracellular Pharmacokinetics
`
`Cladribine is phosphorylated to its 5’-mono-
`phosphate by dCK!”! and deoxyguanosinekinase.|49!
`This latter enzyme is found in mitochondria and a
`high activity is present in samples from brain tu-
`mours and melanomas!*?! and may be of impor-
`tance for the therapeutic effect in these tumours.!*61
`However, deoxyguanosine kinase is a mitochon-
`drial enzyme andit is unclear whether the phos-
`phorylation of cladribine in mitochondria induces
`the same cytotoxic effects as phosphorylation in
`the cytoplasm by dCK. dCK phosphorylates a
`numberof nucleoside analoguesandis the rate lim-
`iting enzyme in the bioactivation of cytarabine
`(ara-C) and fludarabine, another adenosine deami-
`nase resistant purine analogue(fig. 5). Cladribine,
`
`The intracellular pharmacokinetics of the total
`cladribine nucleotide pool have been described in
`hairy cell, chronic lymphocytic, and acute myelog-
`enous leukaemiasafter intravenous, oral, and sub-
`cutaneous administration.b4 The intracellular con-
`centration of the cladribine nucleotides is several
`hundred-fold higher than the plasma concentration
`of the parent drug (fig. 6). Furthermore,the clad-
`ribine nucleotides are well retained in leukaemia
`cells in patients with chronic lymphocytic leukae-
`mia with a terminalty, of around 30 hours when the
`cellular concentration is monitored during 3 to 7
`days (fig. 6). These data support the use of inter-
`mittent administration, which has been gaining
`widespread use lately.!53-55)
`
`© Adis International Limited.All rights reserved.
`
`Clin. Pharmacokinet. 1997 Fel; 32 (2)
`
`5
`
`

`

`125
`Clinical Pharmacokinetics of Cladribine
`
`
`However, the retention of cladribine-nucleo-
`tides in vivo in leukaemia cells of patients with
`acute myelogenous leukaemia appears to be some-
`what lower. During the first 24 hours after admin-
`istration the ty, is 9.0 hours in acute myelogenous
`leukaemia patients as compared to 12.9 hours in
`chronic lymphocytic and 15.1 hours in hairy cell
`leukaemia.3!! Twice-daily administration of clad-
`ribine in acute myelogenous leukaemia might,
`therefore, be worthwhile.
`Recently anew method was developed allowing
`a specific determination of cladribine mono- and
`triphosphate in leukaemia cells in vivo. Prelimi-
`nary data showsthat the pharmacokinetics of the
`mono- and triphosphate are similar. However, the
`relation between the 2 intracellular nucleotides
`seemsto vary!(fig. 7).
`
`4.4 Plasma/Cell Concentration Relationship
`
`The interindividual differences in the intracel-
`lular metabolism of cladribine are important since
`
`there seems to be no direct relationship between
`plasma AUCandintracellular cladribine-nucleo-
`tide AUC. Thus, the concentration of the active
`metabolitesat the targetsite, i.e. the malignant cell,
`cannot be predicted from plasma concentrationsin
`the individual patient. In contrast, the intracellular
`concentration of cladribine-nucleotides appears to
`depend on both the plasma cladribine concentra-
`tion and the activity of dCK in the leukaemia cells
`(fig. 8).671
`
`5. PharmacodynamicRelationships
`
`It was recognised early in the development of
`the drug that the action of cladribine is highly
`schedule dependent.5°>8! Therefore continuousin-
`fusion for 7 days was chosenas the preferred mode
`of administration in the early clinicaltrials.51 How-
`ever, several investigators have shown that inter-
`mittent administration of cladribine works as well
`in both hairy cell leukaemial!®) and chronic lym-
`phocytic leukaemia.!!3.!41
`
`Orally
`10 mg/m?
`
`‘
`
`© Cladribine
`
`Intravenous
`5 mg/m2
`v
`
`
`
`140
`
`a“ NRoO
`
`100
`
`aoO
`
`aoO
`
`SOo
`
`20
`
`
`
`
`
`Plasmaconcentrationofcladribine(nmoi/L)
`
`®@ 2-Chloroadenine
`
`-10
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`Fig. 4. The plasma concentrationof cladribine and its catabolite, 2-chloroadeninein 1 patient after an intravenous 2-hour infusion (5
`mg/m?) and an oral dose (10 mg/m?)of cladribine (Albertioniet al., unpublished data).
`
`© Adis International Limited.All rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`Time(h)
`
`6
`
`

`

`126
`
`Liliemark
`
`
`
`
`
`Fludarabine
`
`Cytarabine
`
`Cladribine
`
`Deoxyadenosine
`
`iatt=)
`
`rereaesened
`
`Vv
`
`v
`
`v
`
`v
`
`Vv
`
`v
`
`Deoxyadenosine
`5'-triphosphate
`
`v
`;
`Cladribine
`5'-triphosphate
`
`Fludarabine
`5'-triphosphate
`
`oa
`/
`Cytarabine
`5'-triphosphate
`
`Deoxyinosine <4
`
`Adenosine
`deaminase
`
`Deoxycoformycin Ft
`(pentostatin)
`
`Fig. 5. The intracellular metabolism of nucleoside analogues. Deoxycytidine kinase phosphorylates the nucleoside analoguesto their
`5’-monophosphates and adenosine deaminase deaminates deoxyadenosine. When pentostatin inhibits adenosine deaminase an
`excess of dATPis formed. Cladribine and fludarabine are resistant to adenosine deaminase. Cladribine is also a substrate for the
`mitochondrial enzyme deoxyguanosine kinase.
`
`In vitro data suggest that there is no simple re-
`lationship between the formation of cladribinetri-
`phosphate intracellularly and antileukaemia ef-
`fect.°) Nor was there any correlation between the
`AUCofthe total cladribine nucleotide pool or
`plasma cladribine concentration and response to
`treatment in chronic lymphocytic leukaemia.7!
`Onthe other hand, a weak (p = 0.028)relation-
`ship was found between the plasma cladribine
`AUCandthe response in hairy cell leukaemia.!!°!
`However, considering the lack of correlation be-
`tween plasma and cellular drug concentrations
`mentioned above,this finding needs to be assessed
`critically and needs to be confirmedbefore its clin-
`ical relevance can be determined.
`
`A weakbutsignificant relationship between the
`activity of dCK in leukaemia cells and response
`was also found by 2 independentgroups.52:60
`Thus, the available data indicates that there are
`indeed unknown factors beyond the bioactivation
`of cladribine which determine the final response.
`They do not allow any conclusion on the usefulness
`of the clinical pharmacokinetics for individ-
`ualisation of the treatment. However,the intracell-
`ular pharmacokinetics of cladribine provides im-
`portant information on the effect of route and mode
`of administration for distribution, bioactivation,
`and retention of the drug at the site of action, the
`tumourcell. Thus, intracellular pharmacokinetics
`are an important tool in decision making on the
`
`© Adis InternationalLimited.All rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`7
`
`

`

`127
`Clinical Pharmacokinetics of Cladribine
`
`
`route and interval of administration in treatment
`protocols.
`
`6. Excretion
`
`About 21 to 32% of intravenously administered
`cladribine is excreted unchanged in the urine
`within the first 24 hours!42,45.61] while renal clear-
`ance is 51% (11 to 85)of the total systemic cladrib-
`ine clearance.!4] After oral administration, 25 +
`21% ofthe dose (corrected for bioavailability) was
`excreted unchangedin the urine and 3.8 + 1.9% as
`CAde. A small amount of CAdeis found in plasma
`also after intravenous administration and 1.5 +
`1.6% of the dose is excreted renally as CAde dur-
`ing the first 24 hours (Lindemalm etal., personal
`correspondence). Since most trial protocols re-
`
`quire that patients have normal hepatic and renal
`function, there are little pharmacokinetic or toxic-
`ity data on the significance of impaired organ func-
`tion. It is therefore not possible to give any recom-
`mendations on dosage modifications in such
`situations.
`
`7. Interaction
`
`The only interaction with cladribine which has
`been well described is with cytarabine. Pretreat-
`ment of patients with cladribine increases the in-
`tracellular accumulation of cytosine arabinoside
`5’-triphosphate (ara-CTP),the active metabolite of
`cytarabine, by 36 to 40%.(62.63! This effect might
`be due to the inhibition of ribonucleotide reductase
`decreasing deoxyribonucleotide pools, in particu-
`
`10000
`
`1000
`
`100
`
`
`
`Concentration(nmol/L)
`
`
` 0.7 mg/kg over 120h
`
`O Cladribine, 2-h infusion
`@ Cladribine, continuousinfusion
`O Cladribine nucleotides, 2-h infusion
`B@ Cladribine nucleotides, continuous infusion
`
`0.14 mg/kg for 2h
`
`JPIttr
`
`
`0
`48
`96
`144
`192
`240
`
`Time (h)
`
`Fig. 6. The concentration of cladribine in plasma (bottom of panel) and the concentration of cladribine nucleotides in leukaemiccells
`(top of panel) in 1 patient with chronic lymphocytic leukaemia given 0.6 mg/kg (= 5 mg/m?) as a 2-hour intravenousinfusions and 4
`weekslater as a continuous infusion of the same dose during 5 days. Theintracellular concentration of cladribine nucleotides was
`determined by measuring cladribine after dephosphorylation of the nucleotides by alkaline phosphatase in methonal extracts of
`leukaemic cells (from Liliemark and Juliusson,?" with permission).
`
`© Adis international Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`8
`
`

`

`128
`Liliemark
`
`
`studies. Traditionally the dose in phaseI trials is
`based on the LD; in mice, 10% of the LDjo in mice
`is used as a Starting dose in patients. The dose is
`then escalated arbitrarily according to a Fibonacci
`scheme!I until the maximum tolerable dose is
`reached.
`
`The pharmacokinetically guided does escala-
`tion concept is based on the assumptionthat there
`is a strongerrelationship between the drug concen-
`tration (AUC)and toxic effects in mice and humans
`than there is betweendose andtoxic effects.!©! The
`AUCat LDjpo is established in mice. Then the AUC
`in humansat the starting dose (10% of the LDj9)is
`determined. The subsequent dose escalation is then
`based on the difference between the murine LD)o
`and human AUC.
`Theoretically this concept is useful for a number
`of different anticancer drugs. However, for antime-
`tabolites, e.g. fludarabine, the concept would have
`been less useful as the AUC in humans at the
`maximum tolerable dose is 10 times lower than
`that of mice at LDjo.!©! Thus, mice appear to be
`less sensitive to the toxic effects of fludarabine.
`This is also the case for cladribine. The Km of the
`main bioactivating enzyme, dCK,is 10 times lower
`for cladribine in human thymocytes as compared
`with thymocytes in mice, while the Vmax is sim-
`ilar. Human dCK therefore phosphorylates clad-
`ribine more efficiently than does the murine en-
`zyme, 661
`In the original phase I trial of cladribine, the
`first 2 patients were given | mg/kg/day as a contin-
`uous infusion for 7 days based on toxicity in
`mice.!6] However, the AUC ofcladribine at LDjo
`in mice is about 50 timeslarger than thatin patients
`at maximum tolerable dose.!®! The therapeutic
`effect was impressive but the patients developed
`bone marrow failure and died. In subsequent pa-
`tients the dosage was decreased to one tenth of the
`starting dose, 0.1 mg/kg/day for 7 days.'®! This
`dose wasalso considered to be the maximumtoler-
`able dose which has been confirmed in more recent
`phase I trials.!4?! Information on only the plasma
`pharmacokinetics in mice and humansis therefore
`not useful for the determination of a safe dosage of
`
`Fig. 7. The concentration of cladribine in plasma and the cladrib-
`ine nucleotides cladribine 5’-monophosphate, and cladribine 5’-
`triphosphate in leukaemic cells in 2 patients after an oral dose
`of 10 mg/m?(Albertionietal.,[56 with permission).
`
`lar deoxycytidine 5’-triphosphate (dCTP) whichis
`an inhibitor of cytarabine (and cladribine) phos-
`phorylation by dCK. Although there are no data,it
`can be suspected that other nucleoside analogues
`which are bioactivated by dCK,e.g. fludarabine
`and gemcitabine, can be the subject of a similar
`interaction with cladribine.
`
`8. Interspecies Differences
`
`Pharmacokinetically guided dose escalation has
`been applied successfully to minimising the num-
`ber of patients needed for phase I dose finding
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`S°
`
`o
`
`1000
`
`100
`
`10
`
`1
`
`2oS
`
`&=
`
`€2 g<
`
`8 10000
`5
`o
`
`1000
`
`400
`
`10
`
`G
`
`
`
`®@ Cladribine 5’-triphosphate
`
`© Cladribine 5'-monophosphate
`QO Cladribine
`
`
`
`
`—T TTT T~
`
`0
`12
`2
`36
`48
`60
`72
`Time (h)
`
`9
`
`

`

`129
`Clinical Pharmacokinetics of Cladribine
`
`
`antimetabolites in humans. This shows that know-
`
`9. Conclusion
`
`ledge about bioactivation is important when phar-
`Pharmacokinetic data on cladribine are slowly
`macokinetically guided dose escalation is em-
`accumulating, and now allow more definite recom-
`ployed in phaseI trials with antimetabolites.
`mendations for its administration. Taken together
`There is also a good correlation between toxic
`with the available clinical data, there is no support
`effects in vivo in humansand the cytotoxic effect
`for the use of continuous intravenous infusion of
`of antimetabolites in vitro. Thus, information on
`cladribine; subcutaneous injection can supersede
`the cytotoxic effect on humancells in vitro is also
`intermittent intravenous administration. Finally,
`useful when decisions are made aboutthe rate of
`due to its variable bioavailability, oral administra-
`tion is recommended when repeated courses are
`dosage escalation in phaseItrials.{67)
`given (i.e. for most indications except hairy cell
`leukaemia).
`
`600
`
`= 500
`:
`=
`400
`£
`= 300
`QO
`3
`<
`S
`
`200
`107
`
`0
`
`0
`
`®
`
`e
`
`e
`
`?2=0.02
`p=0.25
`
`°
`
`e
`
`¢ *.
`e
`oe
`e
`ee
`. ace % ee ‘
`°°, gel, °
`°
`
`ToT
`T
`T
`7 T
`T
`1
`200
`400
`600
`800 1000 1200 1400 1600
`Piasma AUC (nmol/L + h)
`
`e
`
`a
`
`References
`1. Christensen LF, Broom AD, Robins MJ, et al. Synthesis and
`biochemical activity selected 2,6-disubstituted-(2-deoxy-a-
`and §-D-erythro-pentofuranosyl)purines. J Med Chem 1972;
`15: 735-9
`. Giblett ER, Anderson JE, CohenF, et al. Adenosine-deaminase
`deficiency in two patients with severe impaired cellular im-
`munity. Lancet 1972; II (786): 1067-8
`. Seto S, Carrera CJ, Kubota M,et al. Mechanism of deoxy-
`adenosine and 2-chlorodeoxyadenosine toxicity to non-dividing
`hunam lymphocytes. J Clin Invest 1985; 75: 377-83
`. Kazimierczuk Z, Vilpo J, Seela F. Base-modified nucleosides
`related to 2-chloro-2’-deoxyadenosine. Helv Chim Acta
`1992; 75: 2289-97
`. Beutler E. Cladribine. Lancet 1992; 340: 952-6
`. Carson DA, Wasson DB, Beutler E. Antileukemic and immu-
`nosuppressive activity of 2-chloro-2’-deoxyadenosine. Proc
`Natl Acad Sci USA 1984; 2232-6
`. Carson DA, Wasson DB,Kaye J, et al. Deoxycytidine kinase-
`mediated toxicity of deoxyadenosine analogs towards malig-
`nant human lymphoblasts in vitro and towards murine L1210
`leukemia in vivo. Proc Natl Acad Sci USA 1980; 77: 6865-9
`. Bryson H, Sorkin E. Cladribine: a review of its pharmacody-
`namics, pharmacokinetics and therapeutic potential in the
`treatment of haematological malignancies. Drugs 1993; 46:
`872-94
`. Santana V, Mirro J, Cherrie H, et al. Phase I clinical trial of
`2-chlorodeoxyadenosine in pediatric patients with acute leu-
`kemia. J Clin Oncol 1991; 9: 416-22
`. Juliusson G, Heldal D, HippeE,et al. Subcutaneousinjection
`of 2-chlorodeoxyadenosine for symptomatic hairy cell leuke-
`mia. J Clin Oncol 1995; 13: 989-95
`. Piro LD, Elison DJ, Saven A. The Scripps clinic experience
`with 2-chlorodeoxyadenosine in the treatment of hairy cell
`leukemia. Leuk Lymphoma 1994; 14 Suppl. 1: 121-5
`. Juliusson G, Christiansen I, Mgrk-Hansen M,et al. Oral
`cladribine as primary therapy for patients with B-cell chronic
`lymphocytic leukemia. J Clin Oncol 1996; 14: 2160-6
`. Juliusson G,Liliemark J. Long-term survival following cladrib-
`ine (2-chlorodeoxyadenosine) therapy in previously treated
`patients with chronic lymphocytic leukemia. Ann Oncol
`1996; 7: 373-9
`. Saven A, Carrera CJ, Carson D,et al. Chlorodeoxyadenosine
`treatmentof refractory chronic lymphocytic leukemia. Leuk
`Lymph 1991; 5 Suppl: 133-8
`
`500
`
`300
`
`o
`5
`2Qe
`5° 400
`ay
`=o
`os
`2 €
`a
`Sy
`<3 200,
`$8
`eo
`8 2 100
`=
`=
`
`0
`
`e
`
`8
`
`e
`
`e
`
`Ce
`@ a
`
`2=0.21
`r=0.
`p = 0.004
`
`e
`
`@
`
`T
`tT TT 7 74
`200
`400
`600
`800
`1000
`
`0
`
`Plasma AUCfor cladribine x dCk activity
`(umol/L + h x pmol/mg/min)
`
`Fig. 8. (Top) The relationship between the area under the con-
`cenitration-time curve (AUC)of plasmacladribine andintracel-
`lular cladribine nucleotides in 69 patients with chronic
`lymphocytic leukaemia,hairy cell leukaemia and acute myeloid
`leukaemia treated with cladribine 0.085 to 0.22 mg/kg intrave-
`nously or subcutaneously or 0.24 mg/kg orally. (Bottom) The
`relationship betweenintracellular cladribine nucleotides and the
`AUCsof plasmacladribine multiplied by the activity of the phos-
`phorylating enzyme deoxycytidine kinase in leukaemic cells in
`37 patients with chronic lymphocytic leukaemia, hairy cell leu-
`kaemia and acute myeloid leukaemia treated with cladribine
`0.085 to 0.22 mg/kg intravenously or subcutaneously or 0.24
`mg/kg orally.
`
`© Adis InternationatLimited.All rights reserved.
`
`Clin. Pharmacokinet. 1997 Feb; 32 (2)
`
`10
`
`10
`
`

`

`130
`
`Liliemark
`
`15.
`
`Saven A, Emanuele S, Kasty M, et al. 2-chlorodeoxyadenosine
`activity in patients with untreated, indolent non-Hodgkin’s
`lymphoma. Blood 1995; 86: 1710-6
`. Kay A, Saven A, Carrera C, et al. 2-Chlorodeoxyadenosine
`treatment of low-grade lymphomas. J Clin Oncol 1992; 10:
`371-7
`. Liliemark J, Hagberg H, Cavallin-Stahl E, et al. Cladribine (2-
`CdA) for early low grade non-Hodgkin’s lymphoma (LG-
`NHL){abstract}. Blood 1994; 84 Suppl.: 168
`. Liliemark J, Porwit A, Juliusson G. Intermittent infusion of
`cladribine in previously treated patioents with low-grade non-
`Hodgkin’s lymphoma. Leuk Lymphoma.In press
`. Fidias P, Chabner BA, Grossbard ML. Purine analogs for the
`treatment of low-grade lymphoproliferative disorders. The
`Oncologist 1996; 1: 125-39
`Santana V, Mirro J, KearnsC,et al. 2-Chlorodeoxyadenosine
`producesa high rate of complete hematologic remissionsin
`relapsed acute myeloid leukemia. J Clin Oncol 1992; 10:
`364-70
`. Eibschutz B, Baird SM, Weisman MH, et al. Oral 2-chioro-
`deoxyadenosine in psoriatic arthritis: a preliminary report.
`Arthritis Rheum 1995 Nov; 38: 1604-9
`Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic
`progressive multiple sclerosis with cladribine. Proc Natl Acad
`Sci USA 1996: 93: 1716-20
`Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment
`of chronic prgressive multiple sclerosis. Lancet 1994; 334:
`9-13
`
`20.
`
`2
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`3
`
`32.
`
`33.
`
`OberhuberG, Schmid T, Thaler W,et al. 2-Chlorodeoxyadenos-
`ine in combination with cyclosporine prevents rejection after
`allogeneic small boweltransplantation. Transplantation 1994;
`58: 743-5
`Albertioni F, Hassan M, Liliemark J. Kinetics of 2-chloro-2’-
`deoxyadenosine and 2-chloro-2’-arabino-fluoro-2’-deoxyadeno-
`sine in isolated perfused rat
`li