`2-Chlorodeoxyadenosine in Patients With Malignancy
`
`By Alan Saven, Wing K. Cheung, Ian Smith, Michael Moyer, Tricia Johannsen, Esther Rose, Russell Gollard,
`Michael Kosty, William E. Miller, and Lawrence D. Piro
`
`Purpose: This study was designed to evaluate the absolute
`biolavaaiity (F value) of 2-chlorodeoxyadenosine (cladrib-
`ine; 2-CdA) after multiple oral administrations, and the in-
`tersubject variability after oral and 2-hour intravenous (IV) ad-
`ministration schedules in patients with malignancy.
`Patients and Methods: Patients with advanced malig-
`nancies were eligible. There were two treatment cycles;
`during cycle 1, patients received 2-CdA solution at 0.28
`mg/kg/d orally under fasting conditions for 5 consecutive
`days concomitantly with omeprazole, and 4 weeks later
`during cycle 2 patients received 2-CdA as a 2-hour IV infu-
`sion of 0.14 mg/kg/d for 5 consecutive days. Serial blood
`samples for 2-CdA plasma levels were obtained after drug
`administrations on days 1 and 5 during each treatment
`cycle.
`Results: Ten patients completed cycles 1 and 2. The F
`vaTue-ooral 2-CdA measured on days 1 and 5 was 37.2%
`and 36.7%, respectively. For both oral and IV multiple ad-
`ministrations,
`there was no significant accumulation
`
`2-CHLORODEOXYADENOSINE (cladribine; 2-CdA)
`-is a purine analog resistant to the action of adenosine
`deaminase. It is cytotoxic to both resting and proliferating
`lymphocytes,1,2 which may be especially important in the
`treatment of indolent lymphoproliferative disorders such
`as hairy cell leukemia,3-6 chronic lymphocytic leukemia,7-10
`and low-grade non-Hodgkin's lymphoma."l'4 2-CdA has
`been approved in the United States for the treatment of
`hairy cell leukemia as a single 7-day continuous intrave-
`nous (IV) infusion at a dose of 0.09 mg/kg/d. Liliemark
`et al"5 estimated that the oral bioavailability (F value) of
`a phosphate-buffered solution of 2-CdA was 48% when
`given at a dose of 0.14 mg/kg/d for 5 days, and 55% at
`a dose of 0.28 mg/kg/d. The F value of 2-CdA after
`subcutaneous administration was approximately 100%.'"
`In that study, the variability in area under the plasma
`concentration-time curve (AUC) was similar after IV,
`subcutaneous, and oral administrations.
`
`From the Division of Hematology and Oncology, Ida M. and Cecil
`H. Green Cancer Center, Scripps Clinic and Research Foundation,
`La Jolla, CA; and R. W. Johnson Pharmaceutical Research Institute,
`Raritan, NJ.
`Submitted July 5, 1995; accepted October 3, 1995.
`Address reprint requests to Alan Saven, MD, Division of Hematol-
`ogy and Oncology, MS312, Ida M. and Cecil H. Green Cancer
`Center, Scripps Clinic and Research Foundation, 10666 N Torrey
`Pines Rd, La Jolla, CA 92037.
`© 1996 by American Society of Clinical Oncology.
`0732-183X/96/1403-0038$3.00/0
`
`in maximum concentration (C.J), and the intersubject vari-
`abilities (coefficient of variation [CV], . 40%) in C. and
`area under the concentration-time curve from 0 to 24 hours
`[AUCo0.24)] values were comparable for both routes on days
`1 and 5. A three-compartment open model was applied to
`the plasma concentration data after oral and IV administra-
`tions and resulted in good agreement between observed
`and simulated concentration-time profiles. Neutropenia
`was the principal adverse event observed when 2-CdA was
`administered orally and IV.
`Conclusion: The F value of 2-CdA after oral administra-
`tion was approximately 37% and there were no cumulative
`differences in bioavailability observed on multiple dosing
`of the drug. The absorption and disposition characteristics
`of oral 2-CdA were linear and predictable with this dosing
`regimen.
`J Clin Oncol 14:978-983. © 1996 by American So-
`ciety of Clinical Oncology.
`
`We performed this study to determine the absolute
`bioavailability of 2-CdA after multiple oral administra-
`tions in patients with malignancy, and to determine the
`intersubject pharmacokinetic variability after 2-hour IV
`infusions and oral dosings.
`
`PATIENTS AND METHODS
`
`Patient Selection
`Patients with advanced and assessable malignancies (hematologic
`and nonhematologic) that had failed to respond to standard therapy
`were eligible. Inclusion criteria included a life expectancy ý- 3
`months, absence of active infection, adequate renal (serum creatinine
`concentration < 2.0 mg/dL) and hepatic functions (bilirubin, alkaline
`phosphatase, AST, and ALT < two times normal), adequate baseline
`hematologic parameters (absolute neutrophil count > 1.5 x 109/L,
`hemoglobulin concentration > 9 g/dL, and platelet count > 60 X
`109/L), and a Karnofsky performance status - 60. Patients were
`removed from other systemic therapies for at least 4 weeks before
`study entry. This study was approved by the Human Subjects Com-
`mittee of Scripps Clinic and Research Foundation and all patients
`gave written informed consent.
`
`Study Design
`There were two treatment cycles of 2-CdA; during cycle 1 patients
`received oral administrations at 0.28 mg/kg/d for 5 consecutive days,
`and during cycle 2 patients received 2-hour IV infusions at 0.14 mg/
`kg/d for 5 consecutive days, 4 weeks later. The planned accrual was
`for 10 patients to complete both cycles 1 and 2. 2-CdA was supplied
`as a 1.0-mg/mL solution (Leustatin; Ortho Biotech, Raritan, NJ).
`During the oral dosing phase, after an overnight fast, patients
`swished for 20 seconds and then swallowed the appropriate amount
`of 2-CdA solution before being washed down with 50 to 100 mL
`
`978
`
`Journal of Clinical Oncology, Vol 14, No 3 (March), 1996: pp 978-983
`
`Hopewell EX1074
`Hopewell v. Merck
`IPR2023-00481
`
`1
`
`
`
`2-CHLORODEOXYADENOSINE PHARMACOKINETICS
`
`of water. Since it is believed that 2-CdA is unstable in an acid
`environment, patients were placed on omeprazole (Prilosec, Merck
`Sharp and Dohme, West Point, PA) 20 mg/d for 5 days 2 hours
`before receiving of oral 2-CdA. The IV solution was prepared by
`dissolving the calculated dose of 2-CdA in 250 mL of 0.9% sodium
`chloride solution.
`
`Pretreatment and Follow-Up Studies
`History, physical examination, routine laboratory studies, and a
`chest x-ray were performed at baseline. Routine laboratory studies
`included a complete blood cell count (CBC) with a WBC differential,
`a chemistry-24 panel (includes electrolytes, urea, creatinine, glucose,
`total protein, albumin, calcium, phosphate, uric acid, alkaline phos-
`phatase, total bilirubin, AST, and ALT), and urinalysis. In the ab-
`sence of clinically assessable disease, a computed tomographic (CT)
`scan of sites of disease involvement was performed. The history and
`physical examination were repeated before each cycle of 2-CdA
`and monthly thereafter; the CBC count with WBC differential was
`performed daily during therapy and weekly thereafter; the chemistry-
`24 panel was redrawn on the first and fifth day of drug administration
`and monthly thereafter; and the urinalysis was repeated on the first
`day of each 2-CdA cycle. Chest x-ray and CT scans were repeated,
`when appropriate, to determine response status.
`Hematologic and nonhematologic toxicities were evaluated ac-
`cording to Eastern Cooperative Oncology Group (ECOG) toxicity
`criteria."6 Grade 3 and 4 toxicities were deemed significant. Re-
`sponses were determined according to the standard response criteria
`used for evaluation of that particular malignancy. Patients with evi-
`dence of response 4 weeks after the second cycle, and on every
`second cycle thereafter, could continue to receive 2-hour infusions
`of 2-CdA off protocol for a maximum of six cycles.
`
`Pharmacologic Studies
`Serial blood samples for 2-CdA plasma concentrations were ob-
`tained on days 1 and 5 during each treatment cycle. Five-milliliter
`samples of blood were collected and placed into edathamil (EDTA)-
`containing tubes predose, at 15 and 30 minutes after dosing, and at
`1, 1.5, 2, 4, 6, 9, 12, 18, and 24 hours postdose. Tubes were immedi-
`ately put into ice water or refrigerated and the plasma collected by
`centrifugation (5 minutes, 1,000g at 40C) and then frozen at -20 0 C
`until analysis.
`Plasma samples were analyzed for 2-CdA by a sensitive and spe-
`cific, validated high-performance liquid chromatography mass spec-
`trometry (LCMS) assay.17.. ' The samples were extracted before anal-
`ysis, and the range of the standard curve was 0.05 to 20 ng/mL with
`a 0.05 ng/mL limit of quantitation. The interday precision (percent
`coefficient of variation [CV]) of the assay was less than 3% across
`the range of the standard curve. The accuracy of the assay was
`similarly within 3.5% of target concentrations. Quality-control sam-
`ples were run throughout the analysis of unknown samples. The
`stability of 2-CdA in frozen plasma samples was confirmed, together
`with the stability during three freeze-thaw cycles of the samples.
`
`Pharmacokinetic Analysis
`Noncompartmental data analysis. The following model-inde-
`Tx, T(cid:2),
`pendent pharmacokinetic parameters were determined: C
`AUC(o. 24 ), and F, where Cmx was the observed peak plasma concen-
`tration, Tmx was the time at which Cmax occurred, AUC(024) was the
`area under the concentration-time curve during a dosing interval (24
`hours), and F was the bioavailability. AUC(o-24) was calculated using
`
`979
`
`PCNONLIN, version 4.2 (SCI Software, Lexington, KY). F values
`for days 1 and 5 were calculated as dose-normalized oral-to-IV
`ratios of AUC(O-24 ) on days 1 and 5, respectively. CVs for these
`pharmacokinetic parameters were calculated to determine interindi-
`vidual variability.
`Compartmental data analysis. For the IV route a three-compart-
`ment open model was applied to the day 5 IV concentrations using
`PCNONLIN, version 4.2 (model 19). Time elapsed after initiation
`of the first IV infusion was used in the model fitting. The following
`macro constants and pharmacokinetic parameters were determined:
`intercompartmental macro constants (K, 0 , K12 , K21, K13 , and K31);
`half-life for each of the a, P, and y phases of the concentration-
`time curve (T,1/2, T,1 12, and T,0 7 , respectively); AUC from time-
`zero to time-infinity (AUCo,-); plasma clearance (CL); apparent vol-
`ume of distribution in the central compartment (V,); and apparent
`volume of distribution at steady-state (V.).
`The day 5 plasma 2-CdA concentrations after IV infusion were
`used to predict the concentration-time profiles after 2-hour intrave-
`nous infusions of 0.14 mg/kg/d for 5 consecutive days. Macro con-
`stants from individual patients were used in the simulations.
`For the oral route absorption rate constants (K,) for the oral ab-
`sorption of 2-CdA on days 1 and 5 were estimated by fitting a three-
`compartment open model with first-order input to the oral data using
`PCNONLIN, version 4.2. The following four differential equations
`were used to describe the model:
`
`dCp
`dt
`
`= [KaX, -
`
`(Kio + K12 + K13 )*Cp'*V + K 21*X 2 + K31-X 3]/Ve
`
`dX- = Kl2 'C, V - K21" X2
`dt
`
`d = K 3 C,p. V - K31, X3
`
`dX.
`dt
`
`where Cp is the plasma concentration, and X,, X2 , and X3 are
`amounts of drug at the absorption site (the gastrointestinal tract) and
`tissue compartments 2 and 3, respectively. Macro constants esti-
`mated for individual subjects from the day 5 IV data were used in
`the model fitting.
`For the model fitting of day 5 oral data, plasma concentrations
`of 2-CdA were corrected for the contribution of predose 2-CdA
`concentrations by subtracting Co" e-Y' from the 2-CdA concentration
`at each time point, where Co is the 2-CdA plasma concentration at
`the time immediately before dosing on day 5, y is the terminal-
`phase elimination rate constant determined from the day 5 IV data,
`and t is the time postdosing on day 5.
`Plasma 2-CdA concentration-time profiles after oral administra-
`tion of 0.28 mg/kg/d for 5 consecutive days for individual patients
`were simulated using average K, values and individual macro con-
`stants estimated from the day 5 IV data.
`
`RESULTS
`
`Patient Demographics
`
`Eleven patients, six with solid tumors and five with
`hematologic malignancies, entered the study (Table 1).
`
`2
`
`
`
`SAVEN ET AL
`
`E C cC U U CE C CC
`
`Time (hours)
`
`Fig 1. Mean 2-CdA plasma concentrations from 0 to 24 hours after
`oral administration of 0.28 mg/kg/d on days 1 and 5, and IV infusion
`of 0.14 mg/kg/d on days 1 and 5.
`
`lent. The correlations of the model fitting were more than
`0.96 and the Akaike Information Criteriont 9 and Schwarz
`Criterion2 0 criteria were less than 50 for all patients.
`Macro constants and pharmacokinetics constants esti-
`mated from the model fitting are listed in Table 3. These
`macro constants were used to simulate the concentration-
`time profiles after 5 consecutive days of IV and oral
`administrations. There was good agreement between the
`observed and simulated plasma concentration-time pro-
`files for all patients, which indicates that the disposition
`of 2-CdA in humans can be described by a three-compart-
`ment open model. Observed and simulated plasma con-
`centration-time profiles of 2-CdA for a representative pa-
`tient are shown in Fig 2.
`
`980
`
`Table 1. Patient Characteristics
`
`Characteristic
`
`No. of patients
`Sex (male:female)
`Age, years
`Median
`Range
`Prior chemotherapy
`No. of regimens
`0
`1-2
`3-4
`-5
`Malignancy
`Nonhematologic
`Colon
`Ovary
`Biliary
`Kidney
`Hematologic
`AML
`CML, blast crisis
`Lymphoma
`LGL leukemia
`
`Total
`
`11
`6:5
`
`59
`38-68
`
`0
`6
`4
`1
`
`3
`1
`1
`1
`
`1
`1
`2
`1
`
`Abbreviations: AML, acute myeloid leukemia; CML, chronic myeloid leu-
`kemia; LGL, large granular lymphocyte.
`
`Ten patients completed treatment cycle 1 (oral 2-CdA)
`and cycle 2 (IV 2-CdA), while one patient with refractory
`acute myeloid leukemia completed only cycle 1. This
`patient had progressive disease and did not receive cycle
`2. All 11 patients were evaluated for toxicity, but only
`the 10 patients who completed cycles 1 and 2 were in-
`cluded in the pharmacokinetic analysis.
`
`Noncompartmental Data Analysis
`
`Toxicity
`
`Mean plasma 2-CdA concentrations as a function of
`time are shown in Fig 1. Mean model-independent phar-
`macokinetic parameters are listed in Table 2. There was
`no significant accumulation in Cmax (day 5 v day 1) for
`both IV and oral administration of 2-CdA. The F values
`observed on day 1 and day 5 ((cid:2) 37%) were similar. The
`Cm. occurred approximately 1 hour after oral administra-
`tions and 1.86 hours after IV dosing. At half the IV dose,
`the Cmax values after oral administrations were similar
`to those following the 2-hour IV infusions. Intersubject
`variabilities (reflected by the CV values) in Cmx and
`AUC(0-24) values were comparable between IV and oral
`doses on days 1 and 5.
`
`Compartmental Data Analysis
`
`The "goodness-of-fit" of the three-compartment open-
`model to the day 5 IV concentration-time data was excel-
`
`As for hematologic toxicity, among 11 patients who
`received oral 2-CdA, three experienced grade 3 or 4 neu-
`
`Table 2. Model-Independent Pharmacokinetic Parameters
`
`Parameter
`
`Mean + SD
`
`CV (%)
`
`Mean - SD
`
`CV (%)
`
`IV Infusion
`
`Oral Administration
`
`Tm,. (hours)
`Day 1
`Day 5
`Cm,, (ng/mL)
`Day 1
`Day 5
`AUCr 24 (ng- h/mL)
`Day 1
`Day 5
`F (%)
`Day 1
`Day 5
`
`1.86 ± 0.25
`1.83 + 0.37
`
`53.9 + 19.9
`55.8 t 21.8
`
`199 ± 70
`225 + 94
`
`13.4
`20.5
`
`36.9
`39.1
`
`35.1
`42.0
`
`1.08 + 0.40
`0.73 - 0.45
`
`42.4 _+ 19.0
`45.3 + 16.7
`
`146 + 56
`153 + 46
`
`37.2 + 9.8
`36.7 ± 9.0
`
`37.2
`61.8
`
`44.8
`37.0
`
`38.5
`30.1
`
`26.3
`24.5
`
`3
`
`
`
`Hematologic
`Parameter
`
`Neutropenia
`Thrombocytopenia
`Anemia
`
`Table 4. Hematologic Toxicity
`
`Maximum ECOG Toxicity Grade
`
`3"
`
`2
`0
`1
`
`4"
`
`1
`0
`0
`
`3t
`
`3
`0
`1
`
`4t
`
`1
`0
`0
`
`*Cycle 1, oral (n = 11).
`tCycle 2, IV (n = 10).
`
`981
`
`Total No.
`of Patients
`
`5
`0
`2
`
`antibiotics for pneumonia unassociated with significant
`neutropenia.
`Two patients, one with metastatic hypernephroma and
`the other with metastatic ovarian carcinoma, developed
`deep venous thromboses. No patients had alopecia, gas-
`trointestinal, pulmonary, cardiac, renal, or neurologic tox-
`icities.
`
`Responses
`None of six patients with solid tumors responded. Of
`five patients with hematologic malignancies, two re-
`sponded. One patient with chronic myeloid leukemia in
`blast crisis had a more than 50% sustained reduction in
`spleen size and peripheral blood blast count after receiv-
`ing a total of six cycles of 2-CdA. He remains alive 15
`months after first receiving 2-CdA. One patient with T-
`cell large granulocyte lymphocyte leukemia had a partial
`response of 5+ months (> 50% reduction in spleen size
`and an absolute neutrophil count > 1.0 x 109/L) follow-
`ing five courses of 2-CdA.2'
`
`DISCUSSION
`Prolonged exposure of resting peripheral-blood lym-
`phocytes to 2-CdA in vitro resulted in greater lymphocy-
`totoxicity than did brief incubations,1s which led to the
`selection of a continuous IV infusion schedule for the
`initial clinical trials. The 2-CdA dose of 0.09 to 0.10
`mg/kg/d by continuous IV infusion for 7 days has been
`previously demonstrated to be an effective phase II dose. 22
`Pharmacokinetic studies have shown high concentrations
`and prolonged intracellular retention of 2-chlorodeoxyri-
`bonucleotides in chronic lymphocytic leukemia cells fol-
`lowing bolus administration of 2-CdA.23 The 2-hour bolus
`method of 2-CdA administration was developed in an
`attempt to facilitate the outpatient administration of 2-
`CdA and was shown to be effective in 90 patients with
`alkylator-failed chronic lymphocytic leukemia, when a
`comparable total cumulative dose of bolus 2-CdA (21
`patients) to infusional 2-CdA (69 patients) was compared
`(0.1 mg/kg/d by continuous IV infusion for 7 days being
`dose-equivalent to 0.14 mg/kg/d by 2-hour bolus for 5
`
`2-CHLORODEOXYADENOSINE PHARMACOKINETICS
`
`Table 3. Macro Constants and Pharmacokinetic Parameters Estimated
`From Fitting of Data to a Three-Compartment Open Model
`
`Macro Constants
`
`Kio (hours-')
`Ki2 (hours-1)
`K21 (hours-1)
`K13 (hours-1)
`Ka3 (hours-1)
`T1/2, (hours-1)
`T11/2 (hours-')
`T1/2, (hours1-)
`AUCoo. (ng- h/mL)
`Clearance (L/h/kg)
`V. (L/kg)
`V,, (L/kg)
`K. estimated on day 1 (hours-')
`KI estimated on day 5 (hours-')
`Overall mean K. (hours-1)
`
`Mean + SD
`
`3.68 - 3.01
`8.42+ 7.92
`1.19 - 1.43
`1.24 + 1.09
`0.065 +0.030
`0.25 - 0.41
`3.38 + 3.99
`16.4 ± 7.1
`200 ± 83
`0.839 + 0.396
`0.529 + 0.460
`7.72 ± 6.23
`1.36 + 1.46
`2.09 ± 2.36
`1.72 + 1.95
`
`CV
`
`81.8
`94.2
`119.6
`87.8
`46.2
`165.5
`118.1
`43.1
`41.6
`47.1
`86.9
`80.7
`107.7
`113.0
`113.0
`
`Abbreviation: V,, apparent volume of distribution in the central comport-
`ment.
`
`tropenia and one with baseline anemia required RBC
`transfusional support (Table 4). Of 10 patients who re-
`ceived IV infusions of 2-CdA, four experienced grade 3
`or 4 neutropenia and one, also with preexisting anemia,
`required RBC transfusions.
`Regarding infectious toxicities, the patient with grade
`4 neutropenia following oral administration of 2-CdA had
`refractory acute myeloid leukemia and the neutropenia
`was associated with enterococcal bacteremia. Following
`IV 2-CdA, one patient with grade 3 neutropenia and a
`clear chest x-ray received oral antibiotics for bronchitis.
`One patient with non-Hodgkin's lymphoma received IV
`
`.^^
`lUU
`
`10
`
`0.1
`
`aE
`
`I Co
`
`V YX
`
`o4
`
`1 UC
`
`3
`Time (Day)
`
`4
`
`Fig 2. Observed and simulated plasma concentrations after oral
`administration of 0.28 mg/kg/d (0 and --...--, respectively) or IV infu-
`sion of 0.14 mg/kg/d (6 and -,
`respectively) for 5 days for a
`representative subject.
`
`4
`
`
`
`982
`
`SAVEN ET AL
`
`days), the response rates and toxicities of the two regi-
`mens were similar.7 In a study conducted by Liliemark
`et al,' 5 the F value of 2-CdA in three patients given 2-
`CdA at 0.14 mg/kg orally dissolved in phosphate-buffered
`saline was 48% + 8% (mean + SD), whereas in seven
`patients who received 0.28 mg/kg orally it was 55% ±
`17%. In support of the hypothesis that the oral administra-
`tion of 2-CdA could supersede IV infusions if the dose
`was doubled, of 17 patients with untreated chronic
`lymphocytic leukemia treated with oral 2-CdA, seven
`(41%) achieved a complete response and five (29%) a
`partial response.24
`In this study, there were no apparent differences in F
`values observed after multiple dosing on day 1 and day
`5. The F values reported here ((cid:2)
`37%) are lower than
`those reported by Liliemark et a1' 5 (- 55%), who gave
`2-CdA as a 2-hour IV infusion, subcutaneous injection,
`and an oral dose over 3 consecutive days with no washout
`periods between drug administrations. These higher F
`values could be due
`to residual drug from previous
`dose(s). We documented no significant accumulation in
`Cmax for both oral and IV 2-CdA administration and com-
`parable intersubject variabilities (CVs) in Cmax and AUC(0_o
`24) values between oral and IV, on days 1 and 5.
`The apparent volume of distribution of the central com-
`partment ranged from 0.065 to 0.73 L/kg (mean, 0.53 L/
`kg), which indicates that the distribution space of 2-CdA
`in the central compartment ranged from plasma volume to
`total-body water. This suggests a rapid distribution of 2-
`CdA into tissue cells. The large Vss (range, 2.93 to 20.85
`L/kg) also indicates extensive distribution of 2-CdA into
`tissues. The t1/2 for the terminal elimination phase of the
`concentration-time curve ranged from 7.5 to 31.8 hours.
`The excellent agreement between the observed and sim-
`ulated concentration-time profiles after oral and IV admin-
`istration validates the three-compartment open model for
`drug distribution. This indicates that the absorption and
`disposition characteristics of oral 2-CdA are linear and
`predictable with the dosing regimen used in this study.
`The intersubject variability reported after oral adminis-
`
`trations of 2-CdA was similar to that after IV dosing, and
`the F value was consistent between days 1 and 5. These
`results should be interpreted cautiously, since pharmaco-
`kinetic determinations were conducted under well-con-
`trolled conditions. 2-CdA was administered in the fasting
`condition and stomach acid secretion was suppressed by
`omeprazole. Concentration-time profiles after oral admin-
`istration in noninvestigative clinical settings could be sub-
`stantially different from those observed in this study due
`to the effects of stomach acid and food. Any clinical
`application of this route of administration will thus need
`to be accompanied by adherence to these conditions.
`However, other investigators have demonstrated that the
`F value of oral 2-CdA was not enhanced by protection
`against the gastric acid environment using omeprazole.2 5
`It should be pointed out that 2-CdA must first be
`intracellularly phosphorylated by deoxycytidine ki-
`nase to its triphosphate derivative, 2-chlorodeoxyade-
`nosine triphosphate,
`to exert its lymphocytotoxic
`actions,26 and that the relationship between plasma 2-
`CdA concentrations and intracellular 2-chlorodeoxya-
`denosine triphosphate concentrations remains to be
`established. Also, the extent of formation of 2-chloro-
`adenine, an important catabolic product of 2-CdA de-
`tected in the plasma of patients treated with orally
`administered 2-CdA,"8
`indicates that a substantial part
`of the oral dose may be deglycosylated before absorp-
`tion, which may partly explain why the F value of 2-
`CdA was only 37%.27 Data on the formation of 2-
`chloroadenine in the gastrointestinal tract and the oral
`absorption, safety, and pharmacologic activities of 2-
`chloroadenine will need to be more fully elucidated
`before the oral route of administration of 2-CdA is
`used.
`
`ACKNOWLEDGMENT
`We thank Richard Nelson, from the R.W. Johnson Pharmaceutical
`Research Institute, for help in the preparation of the study protocol,
`Mary-Helen Hader for data collection, and the nursing staff of the
`General Clinical Research Center of Scripps Clinic for help in com-
`pleting the study.
`
`REFERENCES
`1. Seto S, Carrera CJ, Kubota M, et al: Mechanism of deoxyaden-
`5. Estey EM, Kurzrock R, Kantarjian HM, et al: Treatment of
`osine and 2-chlorodeoxyadenosine toxicity to nondividing human
`hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA). Blood
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