[CANCER RESEARCH 54, 1235-1239. March 1. 1994]

Pharmacokinetics of Cladribine (2-Chlorodeoxyadenosine) in Childrenwith Acute Leukemia1

Christine M. Kearns, Raymond L. Blakley, Victor M. Santana, and William R. Crom2

Departments of Pharmaceutical Sciences /C. M. K., W. R. C¡,Hematulogy-Oncology ¡V.M. S.], and Molecular Pharmacology ¡R.L. B./, St. Jude Children's Research Hospital,

and Departments of Clinical Pharmacy [W. R. C./, Pediatrics ¡V.M. S./, and Pharmacology [R. L. B.¡,University of Tennessee, Memphis, Tennessee 38101-0318

ABSTRACT

Cladribine is a synthetic purine nucleoside with demonstrated activityin hairy cell leukemia and acute myeloid leukemia. We have studied thepharmacukinetics of this drug in 25 pediatrie patients with acute leukemiatreated with Cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by

continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma, urine, andcerebrospinal fluid cladribine concentrations were determined by a ra-dioimmunoassay with a limit of detection of l UM.An open two-compart

ment model was fit to the plasma concentration data. The mean (SD)clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/in-. When clearance was normalized to body weight (liters/h/kg) it was

negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalizedto body surface area, no significant correlation with age was observed. Themean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nvi and ranged from 23.2-84.5 MM.The terminal phasehalf-life in 22 patients ranged from 14J-25.8 h, with a mean (SD) of 19.7

(3.4) h. The volume of distribution at steady state was highly variable, witha mean (SD) of 356.6 (225.2) liters/m2. None of these parameters was

significantly different between patients in relapse and patients with newlydiagnosed disease. Renal clearance was determined in 7 patients andranged from 34.6-643.6 ml in in nr. with a mean (SD) of 317.9 (208.7)

ml nun in Renal clearance as a percentage of total systemic clearanceranged from 11.0-85.1%, with a mean of 51.0%. In 11 patients, the mean

(SD) cerebrospinal fluid concentration was 6.1 (3.97) MM.a mean of 18.2%of the steady-state plasma concentration. The CSF: plasma concentration

ratio was significantly higher on day 5 (22.7% in 7 patients) than on day4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further

define the metabolic fate of cladribine. In this paper we provide the firstcomprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in thetreatment of patients with meningea! leukemia or malignancies of thecentral nervous system.

INTRODUCTIONCladribine (2-chloro-2'-deoxyadenosine, 2-CDA, Leustatin) is a

synthetic purine nucleoside analogue that is not catabolized by aden-

osine deaminase (1). It is rapidly taken up and phosphorylated bylymphoid and myeloid cells (2, 3); the triphosphate form stronglyinhibits ribonucleotide reducíase(4, 5) and is a good substrate forhuman DNA polymerases (6). Incorporation into DNA results in rapidchain termination such that DNA replication in dividing cells isquickly arrested (4). In nondividing cells, cladribine causes accumulation of DNA strand breaks (7, 8), probably due to inhibition of DNArepair. This in turn results in the depletion of NAD and ATP, probably

Received 10/5/93; accepted 12/30/93.The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

1This research was supported by grant FD-R-(KM)349 from the Orphan Products

Development Office of the U. S. Food and Drug Administration, grants CA 20180(Leukemia Program Project) and CA 21765 (Cancer Center CORE Support) from the N1H.a Center of Excellence grant from the State of Tennessee, and by American LebaneseSyrian Associated Charities (ALSAC).

2 To whom requests for reprints should be addressed, at Pharmaceutical SciencesDepartment. St. Jude Children's Research Hospital, 332 N. Lauderdale. Memphis, TN

38105.

due to poly(ADP) ribosylation of nuclear proteins. The unrepairedDNA damage, like DNA damage caused by other oncolytic agents(9-11), triggers programed cell death (apoptosis) (12, 13).

Cladribine is highly effective in the treatment of hairy cell leukemia(14-16) but may also prove useful to treat lymphoma (17), chronicmyeloid leukemia (18), and chronic lymphoid leukemia (19-21). Inclinical trials at St. Jude Children's Research Hospital, we have dem

onstrated notable activity in children and young adults with relapsedacute leukemia (AML/1 and acute lymphocytic leukemia) (2, 22) andin previously untreated AML.4

There have been few studies of the pharmacokinetics of cladribine.Liliemark and Juliusson (23) described the pharmacokinetics after 2-and 24-h infusions of 0.14 mg/kg in 12 adult patients with lympho-

proliferative diseases. More recently, Liliemark et al. (24) comparedcladribine pharmacokinetics in adult patients to whom the drug wasadministered as a 2-h infusion, s.c., or orally. We previously reported

(22) preliminary pharmacokinetic data from 5 patients with acutemyeloid or lymphoid leukemia in first or later relapse, who were givencladribine by continuous infusion for 5 days at 8.9 mg/irr/day. Noother cladribine pharmacokinetic studies in pediatrie patients havebeen reported. The purpose of the present study was to extend thoseinitial observations to a larger pediatrie population, including bothrelapsed leukemia patients and newly diagnosed patients with AML,and to determine the renal clearance and CSF concentrations of cladribine during a 120-h i.v. infusion.

MATERIALS AND METHODS

Patients and Drug Administration. Demographic characteristics of thepatients arc summarized in Table 1. Twenty-five patients, 12 males and 13

females, ranging in age from 8 months to 23 years (mean and median. 9.6years) were studied. Twelve had relapsed hematological malignancies, 6 eachwith acute myeloid leukemia and acute lymphoid leukemia, and were treatedin a phase II study of cladribine. The clinical results of this study have beenpublished (22). For entry into the phase II study, all patients were required tohave a performance status of 0-2 (Eastern Oncology Cooperative Group cri

teria) and a life expectancy of at least 6 weeks and and be free from uncontrolled infection. Patients who had received prior chemotherapy were requiredto have recovered from any previous treatment toxicity. All patients wererequired to have adequate renal and hepatic function as defined by: blood ureanitrogen, <4() mg/dl; serum creatinine, <1.5 mg/dl; total bilirubin, <1.5 mg/dl;

serum aspartate aminotransferase and serum alanine aminotransferase, both<200 If/liter. Metabolic parameters were required to be within a normal range.

Thirteen study subjects were newly diagnosed patients with acute myeloidleukemia and were treated with one course of cladribine as a single agent in aphase II "therapeutic window" prior to treatment with a conventional combi

nation of daunorubicin, cytarabine, and etoposide. Patients were not requiredto have normal biochemical measurements prior to entry into the study.

Cladribine was synthesized for clinical use by a previously publishedmethod (3). Purity of the final product (>99%) was confirmed by elemental

3 The abbreviations used are: AML, acute myeloid leukemia; CSF, cerebrospinal fluid;K-. volume of the central compartment; Kc, elimination rate constant. /Ccp. intercompart-

ment rate constant; K^. inlercompartment rate constant; Vd^. volume of distribution atsteady state; ti.^ct, initial apparent plasma half-life; f| ¿ß,terminal phase apparent plasmahalf-life.

4 V. M. Santana, C. A. Hurwitz, R. L. Blakley, W. R.Crom, X. Luo. and R. A. Krance.

Complete hématologie remissions induced by 2-chlorodeoxyadenosine children withnewly diagnosed acute myeloid leukemia, unpublished data.

1235

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

PHARMACOKINI.ncS OF CLADRIBINE IN CHILDREN

Table I I'uik'nt characteristics

VariableSexRaceAge

(yr)Wl(kg)Height(cm)Surface

area(m2)Biliruhin(mg/dl)Albumin(g/d!)Aspartate

aminotransferase(IU/liter)Alanincaminolransferase(IU/lilcr)Blood

ure;i nitrogen(mg/dl)Serumcreatinine(mg/dl)Lacticdehydrogenase(IU/liter)Alkaline

phosphatase (IU/liIer)Mean

(range)I2M/13F21

White/4Black9.6(0.7-23.3)39.1

(8.6-110.5)130.5(36.0-279.0)1.18(0.43-2.34)0.57(0.1-2.3)3.8

(2.8-4.7)46.7(19-102)36.0(0.4-125)11.7(2-31)0.76

(0.2-1.4)359.3(82-9257)429.8

(58-861)

analysis, thin-layer chromatography, reverse-phase high-performance liquid

chrornatography. and nuclear magnetic resonance spectroscopy. The compoundwas formulated into a stable pharmaceutical product and tested for sterility andpyrogenicily by the Department of Pharmaceutics, University of Tennessee,Memphis. The final concentration was I mg/ml, in 0.9% Sodium Chloride forInjection (United States Pharmacopeial Convention, Inc.).

Cladribine was administered under Investigational New Drug exemption(IND) 30042 from the U. S. Food and Drug Administration. All patientsreceived 8.9 mg/m2/day cladribine for 5 days by continuous infusion. For

patient administration, the drug was prepared in 100 ml of 0.9% sodiumchloride or 5% dextrose in 0.45% sodium chloride solution. Infusions weredelivered via a pump to ensure a uniform and constant rate of delivery. Freshdrug solutions for infusion were prepared daily.

Blood samples for pharmacokinetic analysis were obtained prior to the startof the infusion (pretreatment sample); 24, 48, 96, and 120 h during the infusion; and 0.5 1, 2, 4, 8, 12, 24, 48, and 72 h after completion of the infusion.Samples during the infusion were obtained by venipuncture from a site opposite the site of drug administration; in patients with multiple-port central

catheters, samples were obtained from the lumen proximal to that used for drugdelivery. The blood was collected in heparinized tubes; the plasma was thenseparated and stored at -20°C until assayed. Urine was collected in 24-h

aliquots during the 5-day infusion. Lumbar puncture was performed on either

day 4 or 5 of the infusion. The sample was frozen for later determination ofcladridinc concentration in the CSF.

Assay and Data Analysis. Cladribine in plasma was measured by radio-

immunoassay as previously described (22). Briefly, individual standard curvesover a concentration range of 1.25-50 nM were prepared for each patient froma pretreatment plasma specimen. The samples were incubated with anti-clad-ribine IgG, [8-'H]cladribine was added, and the mixture was incubated with

excess IgG. The antibody and complex were then precipitated with ammoniumsulfate, and the radioactivity in the washed pellet was measured by scintillationcounting. The intraassay coefficient of variation was 8.7 and 5.6% at 37.5 and225 nM, respectively: the interassay coefficient of variation was 9.8%.

A two-compartment open model was fit to the concentration versus time

data by nonlinear regression using ADAPT II software obtained from theBiomédicalModeling and Simulation Resource, Los Angeles, CA (25). Theparameters of the model were Vc, Kc, Kcp, and /Cpc..Clearance, W5S, and tt/2aand fi/ißwere calculated as secondary parameters.

Administration of the drug as a 120-h infusion and the limited number of

concentration time points immediately postinfusion produced imprecise estimates of the intercompartment rate constants K^ and K^. Therefore, aniterative approach was used to estimate these parameters. First, mean values ofKcp and K^ were determined from maximum likelihood estimates of all fourparameters. Then, in successive analyses, each of these parameters was fixedat this mean value, while the other three parameters were estimated. From theseanalyses, new mean values of Kcp and K^ of 0.52 and 0.05/h were determined.These updated values were then held fixed, and new estimates of Vcand K, forall 25 courses were determined using maximum likelihood estimation. Clearance values from maximum likelihood estimation of all four parameters versusmaximum likelihood estimation in which /Ccpand Kpo were fixed differed onlyslightly. This was undoubtedly because most of the area under the concentration-time curve was during the infusion, and both methods did an equally good

job of describing this portion of the curve.

Renal clearance was calculated by dividing the cladribine urinary excretionrate (amount excreted per unit of time) by the mean plasma cladribine concentration during the urine collection period. All the clearances calculated fromthe individual urine collection periods were averaged for each patient.

RESULTS

The mean (SD) clearance, normalized to body surface area, forthese 25 patients was 39.4 (12.4) liters/h/m2, and clearance rangedfrom 14.4—55.4liters/h/m2. When normalized to body weight, the

mean (SD) clearance was 1.44 (0.62) liters/h/kg and ranged from0.31-2.43 liters/h/kg. The steady-state plasma cladribine concentra

tion was defined as the concentration at 120 h, predicted from eachpatient's individual pharmacokinetic parameters. These values ranged

from 23.2-84.5 nM, with a mean (SD) of 37.7 (17.3) nMand a median

of 29.6 nM.The ti/2ßwas determined for 22 patients who had plasma concen

trations measured for at least 12 h after the end of the infusion. Plasmaconcentrations were determined for only 12 h postinfusion in 2 patients, for 28 h in one patient, and for 48-72 h postinfusion in the other

19 patients. In this group, the mean (SD) fi/^ßwas 19.7 (3.4) h andranged from 14.3-25.8 h. Cladribine appears to distribute into a rela

tively large volume at steady state. In our population, VWSSrangedfrom 32.0-799 liters/m2, with a mean (SD) of 356.6 (225.2) andmedian of 323.0 liters/m2. Pharmacokinetic parameters are summa

rized in Table 2.Clearance, tl/2ß,and Vi/sseach normalized to both body weight and

body surface area were compared with all the demographic variablesshown in Table 1 to determine whether any significant correlationswere present. Only clearance normalized to body weight (liters/h/kg)was correlated with any of these variables. It was highly correlatedwith weight, body surface area, height, and age, all of which arehighly correlated with each other. The predictive abilities (R2) of the

linear regression equation for each of these variables versus clearancewas 58.4, 55.7, 42.6, and 41.8%, respectively (P < 0.0005 in eachcase). The relationship between clearance and age is shown in Fig. 1.Clearance, normalized to body weight, decreased as any of thesemeasures of body size increased. However, when clearance was normalized to body surface area (liters/h/m2), it was only weakly correlated with body weight (tf2=19.6%, P < 0.027).

Serum creatinine and total bilirubin were significant predictors ofclearance (normalized to body weight) with R2 values of 32.7% (P =

0.003) and 20.9% (P = 0.021), respectively. Clearance decreased as

either total bilirubin or serum creatinine increased, as shown in Fig. 2for serum creatinine. However, this relationship was not present forclearance normalized to body surface area. Total bilirubin was also asignificant predictor of the steady-state plasma concentration, although the predictive ability was only 20.7% (P = 0.022). This is

consistent with the relationship between total bilirubin and clearance,since clearance and steady-state plasma concentration are inversely

related. It is noteworthy that all the serum creatinine values were in thenormal range, and only one total bilirubin value was abnormal (2.3

Table 2 Mean (SD> of cladribine phartnacokinelie parameters

PlasmaclearanceLiters/h/kg

Liters/h/m2Steady-state

plasma concentration(/IM)Liters/kg

Liters/m"C'entraidistributionvolumeLiters/kgLiters/m"Kc

(h"1)Terminal

apparent half-life (h)1.44

(0.62)39.4(12.4)32.7(17.3)12.7

(8.5)356.6(225.2)1.11

(0.74)31.3(19.8)2.38

(3.1)19.7(3.4)

1236

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

I'llARMACOKINITICS OF CLADRIBINF. IN CHILDREN

mg/dl) in this study population. However, the lowest cladribine clearance (and highest steady-state plasma concentration) was observed inthis patient. There was no significant difference for any pharmacoki-

netic parameters between the relapsed patients and those previouslyuntreated. There were also no significant differences for any pharma-

cokinetic parameters among the cytological subtypes of acuteleukemia.

Of the 24 patients évaluablefor response to cladribine, there were8 who achieved a complete response, 6 who had a partial response,and 10 who had no response. However, there was no difference forany pharmacokinetic parameter, including clearance, steady-state

plasma concentration, and lt,2ß.among these three response groups.Renal cladribine clearance was determined in 7 patients, for whom

both urinary excretion and plasma concentration data were available.The mean (SD) renal clearance was 317.9 (208.7) ml/min/m2 andranged from 34.6-643.6 ml/min/m2, as shown in Fig. 3. The renal

clearance was an average of 51.0% of the total systemic clearance, butthe percentage of total clearance accounted for by renal clearanceranged from 11.0-85.1%. When renal clearance was plotted against

serum creatinine, there was an apparent negative linear relationshipbetween serum creatinine and renal cladribine clearance (renal clearance decreased with increasing serum creatinine). However, this correlation did not achieve statistical significance, due to the smallsample size.

Cladribine CSF concentrations were determined for 10 patientson either day 4 (3 patients) or day 5 (7 patients) of the infusion. Themean (SD) CSF concentration was 6.1 (3.97) nM and ranged

2.5 r

S? 2.0

1.5

gO

S »

0.08 12 16

Age (years)

20 24

Fig. 1. Cladribine clearance, normali/ed to body weight. ver.vH.vage (R2 = 41.8%, P <

0.0005) in 25 leukemia patients.

2.5

2.0

1.5

g 1-0Og»

0.00.0 0.2 0.4 0.6 0.8 1.0

Serum Creatinine (mg/dL)

1.2 1.4

Fig. 2. Cladribine clearance, normalized to body weight, versus serum creatinine(R- = 32.7%, P = 0.003) in 25 leukemia patients.

700

600

500

400

300

200

100

0Fig. 3. Cladribine renal clearances in 7 acute leukemia patients.

40 r

35

£. 30

25 h

20

Õ 15

u)o

10

5 •¿�

4 5

Day of CSF Sample

Fig. 4. The CSF to plasma ratio of cladrihine (shown as a percentage) vcr.vu.vthe dayon which the CSF sample was obtained. Solid line, median ratio observed on each day.These medians were significantly different (P = 0.03) by the nonparamctric Mann-

Whitney U test.

from 1.68-19.75 nM. The mean (SD) CSF:plasma concentration

ratio (expressed as a percentage) was 18.2% (10.0). There appeared tobe a relationship between plasma and CSF concentrations, althoughCSF concentrations were highly variable at any given steady-state

plasma concentration. The highest CSF concentration, 14.75 nw, wasachieved in the patient with the highest steady-state plasma concen

tration, 84.5 nin. However, 7 of the patients had plasma concentrationsbetween 20 and 30 nM, with concurrent CSF concentrations in therange of 2.25-11.25 nM. In addition, there appeared to be a time-

dependent effect on the CSF cladribine concentrations achieved. In 7patients from whom CSF samples were obtained on day 5 (the last dayof the infusion), the mean CSF:plasma ratio was 22.7% (range 12.4—

38.0%). In contrast, for the 3 day 4 patients, the mean CSF:plasmaratio was 7.6% (range, 5.5-9.4%). This difference was statisticallysignificant (P = 0.03, Mann-Whitney U test), as shown in Fig. 4.

DISCUSSION

The present study represents the first detailed pharmacokineticstudy of cladribine in a pediatrie patient population, as well as the firstpharmacokinetic study of cladribine administered as a prolonged120-h infusion. Previously, investigators (23, 24) have examined the

pharmacokinetics of cladribine in adults only. In those studies,Liliemark et al. (23, 24) described the disposition of cladribine following 2- and 24-h i.v. infusions, as well as after s.c. and oral administration. Plasma drug concentrations were determined by high-performance liquid chromatography (26). In addition, a 3-compartmentmodel was fit to the data following the 2-h i.v. infusion. Despite these

1237

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

PHARMACOKINETICS OF CLADRIBINE IN CHILDREN

methodological differences, very comparable results were obtained.The mean (SD) clearances following the 2-h infusion in the two

studies by Liliemark et al. (23, 24) (calculated from data in the paper)were 0.74 (0.30) liters/h/kg and 0.93 (0.33) liters/h/kg, respectively,and following a 24-h infusion in the same patients in the second study,

the mean (SD) clearance was 1.08 (0.47) liters/h/kg. These valuescompare well with our mean clearance of 1.44 liters/h/kg, especiallywhen the higher clearances in younger children are considered. In 7patients in our study who were 15 years of age or older, the mean (SD)clearance was 0.71 (0.42) liters/h/kg, and values ranged from 0.31-

1.27 liters/h/kg, which are very similar to data from the studies ofLiliemark et al. The mean plasma concentration for the 24-h infusion

in the first study of Liliemark et al. (23) was 22.5 nM,compared to ourmean plasma concentration of 37.7 nin. These differences in steady-

state concentrations, despite similar plasma clearances, are accountedfor by the lower drug dosage used by Liliemark et al. of 0.14 mg/kg/24 h, which was about one-half the dosage administered in our

study.In contrast, the mean (SD) terminal half-life following the 2-h

infusion was 6.7 (2.5) and 9.9 (4.6) h in the studies of Liliemark et al,compared to our value of 19.7 (3.4) h. This difference is probably dueto the differences in drug administration and blood sampling betweenthe studies of Liliemark et al. and our work, as well as somewhatgreater sensitivity of our radioimmunoassay (=0.2 nvi), which permits

measurement of plasma concentrations for a longer time, resulting ina longer terminal half-life.

Our observation that plasma clearance normalized to body weight islower in older children and young adults than in young children isentirely consistent with observations for other anticancer drugs (27,28). This finding suggests that differences in cladribine clearancerelated to body size and/or age are more completely accounted forwhen drug dosage is based on body surface. Therefore, drug dosagesbased on body surface area are more likely to achieve a consistentplasma concentration across the age range seen in this study thandosages based on body weight. This may be due to the relative size ofclearing organs (liver and kidneys) relative to total body size. It hasbeen suggested that for some drugs the "functional hepatic mass,"

which approximates liver volume, is a major determinant of hepaticdrug metabolism. Liver volume estimated by ultrasound studies issimilar in children and adults when expressed as a percentage of bodysurface area but is greater in children when normalized to bodyweight, with the ratio of liver volume to weight decreasing withincreasing age (39). Therefore, these results suggest that dosagesbased on body weight (in the pediatrie population) will yield lowerserum concentrations in younger patients, while dosages based onbody surface area are more likely to result in similar concentrations inpatients of different ages.

The lack of any predictive relationship between drug dispositionand demographic or biochemical variables limits the ability to usethese data to adjust dosages (based on body surface area) for differences in renal or hepatic function or on the basis of race or sex.However, the lack of significant correlations is not surprising sincealmost all of these patients had biochemical measurements in thenormal range, which was a requirement for study enrollment. Similarly, the lack of a relationship between drug exposure and eithereffect or toxicity is not surprising. Regardless of systemic plasmaexposure, all of the patients experienced grade 3 or grade 4 hemato-

logical toxicity at this dosage. Intrinsic sensitivity of the malignantcells to the drug is probably more important than systemic exposure inproducing therapeutic responses. Decreased cellular sensitivity maybe due, for example, to reduced kinase activity, resulting in lowerintracellular conversion of cladribine to the active nucleotide form or

to reduced activity of the various DNA polymerases that are thetargets of cladribine.

This is the first clinical study which has measured the renal clearance of cladribine. On average, about half the plasma clearance ofthis drug is accounted for by excretion of unchanged drug in theurine. However, our data from 7 patients suggests that this may behighly variable, with as little as 10% or as much as 85% of the totaldrug clearance accounted for by renal clearance. The fate of theremainder is unknown, because no metabolites have been identified inurine or plasma. It is possible that the remainder of the drug is boundto tissues or intracellular sites. Also, our observation of the lowestcladribine clearance in our only patient with an elevated serum indirect bilirubin suggests that biotransformation by hepatic enzymes mayplay a role in drug elimination. However, additional work needs to bedone to determine the role and importance of nonrenal clearancemechanisms.

One previous report by Saven et al. (30) described CSF concentrations of cladribine. In their study, 3 patients achieved CSF concentrations of 2.2-24.7 nMat dosages of 0.1, 0.15, and 0.2 mg/kg/day by

continuous i.v. infusion. These values are similar to our mean CSFconcentration of 6.54 nM observed in 10 patients (range, 2.25-14.75

UM). In addition, we observed an apparent time dependency on thepenetration of cladribine into the CSF, with higher concentrationsrelative to plasma concentrations after 5 days of continuous infusion,compared to 4 days. These results must be interpreted with extremecaution, however, since so few observations (3 on day 4 and 7 on day5) are available. Nevertheless, transfer of cladribine into the CSF maybe a "membrane-limited" process rather than a "flow-limited" one.

This suggests that the amount of drug reaching the CSF is directlyrelated to the length of time a concentration gradient is maintainedbetween the plasma and the CSF. In the paper by Saven et al. (30), itis not specified on which day of the 7-day infusion the CSF specimens

were obtained. In combination, these results suggest a potential rolefor systemic cladribine therapy in the treatment of primary malignancies of the central nervous system, as well as for meningeal leukemia.However, much more work is needed to identify the factors (plasmaconcentration, length of exposure, etc.) which influence the amount ofdrug reaching the central nervous system.

In summary, this paper provides the first comprehensive descriptionof cladribine pharmacokinetics in children and the first renal clearancedata in patients. Clearance normalized to body weight is higher inchildren than adolescents or adults, but this difference is not seenwhen clearance is normalized to body surface area. The potentiallycytotoxic cladribine concentrations achieved in the CSF provide arationale for the use of this drug in treating malignancies of the centralnervous system. Additional investigation is needed to determine themetabolic fate of cladribine as well as to define a relationship betweensystemic drug exposure and tumor response or toxicity.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the technical expertise of Debra

Jackson.

REFERENCES

1. Carson, D. A., Wasson, D. B., Kaye, J., Ullman, B., Martin, D. W., Jr., Robins, R. K.,and Montgomery, J. A. Deoxycytidine kinase-mediated loxicity of deoxyadenosineanalogs toward malignant human lymphoblasts in vitro and toward murine I I 'Hi

leukemia in vivo. Proc. Nati. Acad. Sci. USA, 77: 6865-6869, 1980.2. Santana, V. M., Mirro, J., Jr., Harwood. F. C., Cherrie, J., Schell, M., Kalwinsky, D.,

and Blakley, R. L. A phase I clinical trial of 2-chlorodeoxyadenosine in pediatriepatients with acute leukemias. J. Clin. Oncol., 9: 416-422, 1991.

3. Avery, T. L., Rehg, J. E., Lumm. W. C., Harwood, F. C., Santana, V. M., and Blakley,R. L. Biochemical pharmacology of 2-chlorodeoxyadenosine in malignant humanhematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug

1238

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

PHARMACOKINETICS OF CLADRIBINE IN CHILDREN

combinations in mice. Cancer Res., 49: 4972-4978, 1989.

4. Griffig, J., Koob, R., and Blakley, R. L. Mechanisms of inhibition of DNA synthesisby 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res., 49: 6923—

6928, 1989.5. Parker. W. B., Bapat. A. R.. Shen, J. X., Townsend, A. J., and Cheng, Y-C. Interaction

of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNAprimase, and ribonucleotide reducíase.Mol. Pharmacol., 34: 485—491.1988.

6. Chunduru, S. K., Appleman, J. R., and Blakley, R. L. Activity of human DNApolymerases a and ßwith 2-chloro-2'-deoxyadenosine 5'-triphosphate as a substrate

and quantitative effects of incorporation on chain extension. Arch. Biochem. Bio-phys., 302: 19-30, 1993.

7. Seto, S., Carrera, C. J., Kubota, M., Wasson, D. B., and Carson, D. A. Mechanism ofdeoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J. Clin. Invest., 75: 377-383, 1985.

8. Carrera, C. J., Terai, C., Lotz, M., Curd, J. G., Piro, L. D„Beutler, E., and Carson, D.A. Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro andin vivo. A novel approach to immunosuppressive therapy. J. Clin. Invest., 86: 1480-

1488, 1990.9. Loten, J. and Sachs, L. Hematopoietic cytokines inhibit apoptosis induced by trans

forming growth factor ßland cancer chemotherapy compounds in myeloid cells.Blood, 80: 1750-1757, 1992.

10. Barry, M. A., Behnke, C. A., Eastman, A. Activation of programmed cell death(apoptosis) bycisplatin, other anticancer drugs, toxins and hyperthermia. Biochem.Pharmacol., 40: 2353-2362, 1990.

11. Walker, R. W., Smith, C., Youlade, T.. LeBlanc, J., Whitfield, J. F., and Sikroska, M.Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes.Cancer Res., 57.-1078-1085, 1991.

12. Carrera, C. J., Piro, L. D., Saven, A., Beutler, E., Terai, C., and Carson, D. A.2-Chlorodeoxyadenosine chemotherapy triggers programmed cell death in normaland malignant lymphocytes. In: R. A. Harkness (ed.), Furine and Pyrimidine Metabolism in Man. Vol. VII, p. 15. New York: Plenum, 1991.

13. Robertson, L. E., Chubb, S., Meyn, R. E., Story, M., Ford, R., Hittleman, W. N., andPlunkett, W. Induction of apoptotic cell death in chronic lymphocytic leukemia by2-chloro-2'-deoxyadenosine and 9-ß-D-arabinosyl-2-fluoroadenine. Blood, 81: 143-

150, 1993.14. Piro, L. D., Carrera, C. J., Carson, D. A., and Beutler, E. Lasting remission in

hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N. Engl.J. Med., 322: 1117-1121. 1990.

15. Beutler, E. Drug profiles. Cladribine (2-chlorodeoxyadenosine). Lancet, 340: 952-956, 1992.

16. Juliusson, G., and Liliemark, J. Rapid recovery from cytopenia in hairy cell leukemiafollowing treatment with 2-chloro-2'-deoxyadenosine (CdA): relation to opportunistic

infections. Blood, 79: 888-894, 1992.

17. Kay, A. C., Saven, A., Carrera, C. J., Carson, D. A., Thurston, D., Beutler, E., and Piro,L. D. 2-Chlorodeoxyadenosine treatment of low-grade lymphoma. J. Clin. Oncol., 70:371-377, 1992.

18. Saven, A., Figueroa, M. L., Piro, L. D., and Beutler, E. Complete hematologicalremissions in chronic myelogenous leukemia (CML) following 2-chlorodeoxyadenosine (2-CdA) (abstract). Proc. Am. Soc. Clin. Oncol., //: 261, 1992.

19. Piro, L. D., Carrera, C. J., Beutler, E., and Carson, D. A. 2-Chlorodeoxyadenosine, aneffective new agent for the treatment of chronic lymphocytic leukemia. Blood, 72:1069-1073, 1988.

20. Saven, A., Carrera, C. J., Carson, D. A., Beutler, E., and Piro, L. D. 2-Chlorodeoxyadenosine treatment of refractory chronic lymphocytic leukemia. Leuk. Lymphoma, 4(Suppl.): 133-138, 1991.

21. Juliusson, G., and Liliemark, J. High complete remission rate from 2-chloro-2'-

deoxyadenosine in previously treated patients with B-cell chronic lymphocytic leu

kemia: response predicted by rapid decrease of blood lymphocyte count. J. Clin.Oncol., 77: 679-689, 1993.

22. Santana, V. M., Mirro, J., Jr., Kearns, C., Schell, M. J., Crom, W., and Blakley, R. L.2-Chlorodeoxyadenosine produces a high rate of complete hématologieremission inrelapsed acute myeloid leukemia. J. Clin. Oncol., 10: 364-370, 1992.

23. Liliemark, J., and Juliusson, G. On the pharmacokinetics of 2-chloro-2'-deoxyadeno

sine in humans. Cancer Res., 5/: 5570-5572, 1991.

24. Liliemark, J., Albertioni, F., Hassan, M., and Juliusson, G. On the bioavailability oforal and subcutaneous 2-chloro-2'-deoxyadenosine in humans: alternative routes of

administration. J. Clin. Oncol., 10: 1514-1518, 1992.25. D'Argenio, D. Z., and Schumitzky, A. A program package for simulation and param

eter estimation in pharmacokinetic systems. Comput. Prog. Biomed., 9: 115-134,

1979.26. Liliemark, J., Pettersson, B., and Juliusson, G. Determination of 2-chloro-2'-deoxy-

adenosine in human plasma. Biomed. Chromatogr., 5: 262-264, 1991.27. Crom, W. R., Glynn-Barnhart, A. M.. Rodman, J. H., Teresi, M. E., Kavanagh, R. E.,

Christensen, M. L., Relling, M. V., and Evans, W. E. Pharmacokinetics of anticancerdrugs in children. Clin. Pharmacokinet., 12: 168-213, 1987.

28. Evans, W. E., Petros, W. P., Relling, M. V, Crom, W. R., Madden, T., Rodman, J. H.,and Sunderlund, M. Clinical pharmacology of cancer chemotherapy in children.Pediatr. Clin. North Am., 36: 1199-1230, 1989.

29. Evans, W. E., Relling, M. V, De Graaf S., Rodman, J. H., Pieper, J. A., Christensen,M. L, and Crom, W. R. Hepatic drug clearance in children: studies with indocyaninegreen as a model substrate. J. Pharmacol. Sci., 78: 452-456, 1989.

30. Saven, A., Kawasaki, H., Carrera, C. J., Waltz, T., Copeland, B., Zyroff, J., Kosty, M.,Carson, D. A., Beutler, E., and Piro, L. D. 2-chlorodeoxyadenosine dose escalation innonhematologic malignancies. J. Clin. Oncol., 11: 671-678, 1993.

1239

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from

1994;54:1235-1239. Cancer Res   Christine M. Kearns, Raymond L. Blakley, Victor M. Santana, et al.   Children with Acute LeukemiaPharmacokinetics of Cladribine (2-Chlorodeoxyadenosine) in

  Updated version

  http://cancerres.aacrjournals.org/content/54/5/1235

Access the most recent version of this article at:

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/54/5/1235To request permission to re-use all or part of this article, use this link

Research. on December 12, 2020. © 1994 American Association for Cancercancerres.aacrjournals.org Downloaded from