(CANCER RESEARCH 50. 6525-6528. October 15. 1990|
Plasma Pharmacokinetics and Cerebrospinal Fluid Concentrations of Idarubicin and
Idarubicinol in Pediatrie Leukemia Patients: A Childrens Cancer Study Group
Report1
Joel M. Reid, Thomas W. Pendergrass, Mark D. Krailo, G. Denman Hammond, and Matthew M. Ames2
Division of Developmental Oncology Research, Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905 [J. M. R., M. M. A./; Division of
Hematology/Oncology, Department of Pediatrics, L'nirersity of Washington (and Children's Hospital and Medical Center), Seattle, Washington 98105 [T. H. P.]; and
University of Southern California School of Medicine, Los Angeles, California 91101 [M. D. A'., G. D. H.]
parent drug (6, 10, 11). Idarubicinol may play a role in the
antitumor activity of idarubicin.
In adult clinical trials, idarubicin was active in the treatment
of lymphocytic and myelogenous leukemias (12). Based on the
preclinical and adult clinical data, the CCSG' initiated a phase
ABSTRACT
Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue
with striking in vitro and in vivo activity against murine leukemias. Based
on activity in adults with acute lymphoblastic leukemia, the Childrens
Cancer Study Group initiated studies to evaluate idarubicin in children
I trial of idarubicin in children with second or subsequent
with leukemia in second or subsequent relapses. As part of those studies,
relapses
of acute lymphocytic and acute myelogenous leuke
we have characterized the plasma pharmacokinetics of idarubicin and the
mias. We now report the plasma pharmacokinetics of idarubicin
major circulating metabolite idarubicinol in 21 patients. Idarubicin
plasma elimination was described by a three-compartment open model and the alcohol metabolite idarubicinol as well as the presence
following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks
of idarubicinol in CSF of these children following administra
and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45
tion of idarubicin to patients participating in this phase I trial.
mg/m2). There was substantial variability in idarubicin elimination among
patients, but no indication of dose-dependent or of schedule-dependent
changes in pharmacokinetic parameters. The mean terminal half-life,
MATERIALS AND METHODS
total body clearance, and steady state volume of distribution were 17.6
h, 679 ml min nr. and 562 1 nr. respectively. Idarubicinol elimination
Chemicals. Idarubicin, idarubicinol, and epirubicin were supplied by
was prolonged compared to that of the parent drug with a terminal halfAdria laboratories. HPLC grade acetonitrile and methanol (EM Sci
life of 56.8 h. This metabolite clearly accumulated in plasma during the
ence), desimipramine (Sigma Chemical Co.), and monobasic potassium
3 days of treatment on the schedule of daily for 3 days. Urinary recoveries
phosphate (Baker analyzed. J. T. Baker) were used as received. Stock
(48 h) of idarubicin and idarubicinol after a single dose of idarubicin were solutions of drugs and internal standards were prepared in HPLC
2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cérébromobile phase (see below) containing desimipramine (10 ng/ml) in
spinal fluid samples obtained 18-30 h after administration. In marked
silanized glass vials.
contrast, idarubicinol was detected in 20 of those 21 samples. Concentra
Patients. The 21 patients eligible for this study were between 1 and
tions in the 20 samples varied from 0.22-1.05 ng/ml with a mean value
21 years of age with leukemia in second or subsequent bone marrow
of 0.51 ng/ml.
relapse and had failed higher priority CCSG protocols or other standard
therapy. Patients had a Karnofsky performance status >30, normal
organ function, and a life expectancy of 4 weeks or more. All patients
INTRODUCTION
had recovered from the toxicity of previous therapy, had received <325
mg/m: of anthracyclines, had not previously received idarubicin, and
Idarubicin (4-demethoxydaunomycin, Fig. 1) is an anthracy
cline analogue currently under evaluation for the treatment of
adult and pediatrie leukemias. Early clinical interest in this
analogue was based on greater cytotoxicity against murine (1,
2) and human (3, 4) tumor cells in culture when compared to
other anthracyclines. For example, idarubicin was 27- to 100fold and 65- to 200-fold more toxic than daunomycin and
doxorubicin, respectively, against HeLa cells (5). We recently
determined that the 50% inhibitory dose values for idarubicin
were 2- to 4-fold lower than those of daunomycin against human
lymphoblastic (CCRF-CEM) and human myelogenous (K-562)
leukemia cells in culture (6). Idarubicin was also more active in
vivo against murine LI210 and P388 tumors when compared
to daunomycin and doxorubicin (7, 8). Also of interest were
findings in our laboratory and others that the major circulating
metabolite of idarubicin, idarubicinol (Fig. 1), has substantial
cytotoxic activity against tumor cells (2, 6, 9). This is in contrast
to alcohol metabolites of other anthracyclines, such as dauno
mycin and doxorubicin, which are much less active than the
Received 3/29/90; accepted 7/13/90.
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 with 18 L'.S.C. Section 1734 solely to indicate this fact.
1This work is supported in part by the National Cancer Institute. DHHS
Grant CA 28882. and Adria Laboratories.
2To whom requests for reprints should be addressed, at 200 First Street. S.W.,
Rochester. MN 55905.
had not received anticancer therapy for at least 3 weeks (unless their
disease progressed during that period as evidenced by an increasing
peripheral blast cell count or an increasing percentage of marrow blast
cells). Patients were required to have measurable disease without clinical
signs of CNS relapse at the initiation of treatment. Three patients were
found to have blast cells in their CSF. Fourteen of the 21 patients had
received CNS radiation prior to study, and 15 had received intrathecal
therapy. Signed, institutionally approved informed consent was ob
tained from all patients and/or their guardians. Idarubicin (10. 12.5,
13.5. and 15 mg/m2) was administered by i.v. infusion (10-45 min)
once daily for 3 days every 3 weeks or once weekly for 3 weeks.
Samples. Patient whole blood samples (4 ml) were collected in
heparinized tubes and cooled immediately in ice-water. Plasma was
isolated by low speed centrifugation, transferred to plastic tubes,
capped, and immediately frozen. Samples were obtained prior to drug
administration and 0.5, I, 2, 4, 6, 8, 12, 24, and 48 h after drug
administration on day 1 of the schedule of once weekly for 3 weeks or
on day 3 of the schedule of once daily for 3 days every 3 weeks. Samples
were also obtained prior to drug administration and 12 h after drug
administration on days 1 and 2 of the once daily for 3 days every 3
weeks schedule.
As specified in the protocol, lumbar puncture was done 18-30 h
after the first dose during the once weekly for 3 weeks schedule and
3The abbreviations used are: CCSG. Childrens Cancer Study Group; CSF,
cerebrospinal fluid; HPLC, high performance liquid chromatography; CNS, cen
tral nervous system: C/r«.total body clearance; t\/ii, mean terminal half-life; Vd„,
steady state volume of distribution.
6525
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IDARUBICIN AND 1DARUBICINOL PHARMACOKINETICS
O
R0II
IS
o>
u
CCH3CompoundIdarubicin
c
0)
OH
l
CHCH3
Idarubicinol
o
IS
NH2
Idarubicinol
Fig. 1. Structures of idarubicin and idarubicinol.
Idarubicin
after the third dose during the once daily for 3 days every 3 weeks
schedule in patients without signs or symptoms of CNS disease. An
aliquot ofthat clinical CSF specimen (2 ml) was frozen for determina
tion of idarubicin and idarubicinol.
Urine was collected only during the weekly schedule in separate
containers from 0-24 h and from 24-48 h after the administration of
the first dose of idarubicin. The specimens were refrigerated during the
collection period. Following each collection period the total volume
was noted and an aliquot frozen for determination of idarubicin and
idarubicinol.
Sample Preparation. Epirubicin ( 100 ng/20 ii1) was added to standard
curve or thawed patient plasma aliquots (1.5 ml) as internal standard.
Plasma was diluted with an equal volume of 25 mivi potassium phos
phate buffer (pH 3.0). All three molecules were isolated from biological
samples by solid phase extraction with I-ml Baker ds SPE columns.
Prior to sample addition, columns were rinsed with 2 ml each methanol,
distilled water, and 25 m.M potassium phosphate buffer (pH 3.0).
Following sample application, columns were washed with 2.5 ml 25
mM potassium phosphate buffer (pH 3.0), 2 ml distilled water, and the
three anthracyclines eluted with 1 ml methanol/25 mM potassium
phosphate buffer, pH 3.0 (9/1). Solvent was evaporated under a gentle
stream of nitrogen and the residue reconstituted in 0.25 ml mobile
phase containing desimipramine (10 Mg/ml) added to prevent adsorp
tion to glassware. CSF (2 ml) and urine (0.1 ml) diluted with normal
saline (0.9 ml) were extracted by the same column procedure and the
residue was reconstituted in 0.2 ml (CSF) or 0.25 ml (urine) mobile
phase. Recoveries of idarubicin, idarubicinol, and epirubicin from
plasma were 92, 91, and 93ci, respectively. Idarubicin and idarubicinol
concentrations were determined by fit of unknown sample drug/internal
standard peak height ratios to the linear regression equations derived
from standard curves.
HPLC Assay. Idarubicin and idarubicinol were determined by a
modification of the reverse phase HPLC procedure of Pizzorno et al.
(13). Separation was achieved on an IBM CigHPLC column (25 cm x
4.6 mm i.d.; 5 ^m) and Brownlee guard column (15 x 3.2 mm i.d.: 7
urn). The mobile phase consisted of acetonitrile, methanol, and 50 mM
potassium phosphate buffer, pH 4.5 (45/10/45). Eluting materials were
detected by fluorescence (excitation wavelength, 254 nm: emission
wavelength, >440 nm). Plasma and urine standard curves were linear
over the range of 0.25-100 ng/ml for idarubicin and idarubicinol. CSF
standard curves were linear from 0.15-5.0 ng/ml. Representative pa
tient plasma chromatograms from blood samples obtained prior to and
after administration of idarubicin are illustrated in Fig. 2.
Analysis of Pharmacokinetic Data. Plasma idarubicin concentration
data were fitted to the equation Y = Ae~'" + Be'"1 + Ce"1' by nonlinear
regression using the program NONLIN (14) on a CDC Ciber 170-720
computer equipped with interactive graphic analysis. A weighting factor
of \/Y, where Y is the plasma concentration at time / following
administration of the drug was used. A, B, and C are intercepts at t =
0 and a, ß,and y are the disposition rate constants. The plasma
elimination half-life of idarubicinol was estimated by graphic analysis.
Values of CITs and yd,, were adjusted for duration of infusion and
multiple dosing (15).
j_
6
8
10
12
14
16
Time, min
Fig. 2. Chromatograms of patient plasma extracts from samples obtained
prior to (top) and 24 h after (bottom) idarubicin administration (12.5 mg/m2).
Concentrations of idarubicin and idarubicinol arc 24 and 11 ng/ml. respectively.
1000 r
Idarubicinol
10.0
O)
C
ù,Idarubicin
Days after first dose
Fig. 3. Plasma profile of idarubicin (O) and idarubicinol (•)following once
eekly for 3 weeks administration of 10 mg/m2 idarubicin to patient G2.
RESULTS
Plasma Pharmacokinetics. Plasma elimination of idarubicin
and idarubicinol were characterized following i.v. administra
tion of idarubicin (10-45 min) on the once daily for 3 days
every 3 weeks and the once weekly for 3 weeks schedules.
Representative patient plasma profiles for idarubicin and ida
rubicinol following administration of idarubicin once weekly
for three weeks and once daily for three days are shown in Figs.
3 and 4, respectively. Individual patient pharmacokinetic data
are summarized in Table 1. Plasma elimination of idarubicin
was described by a three-compartment open model with ii/27,
CljH, and VdKvalues of 17.6 h, 679 ml/min/nr, and 562 liters/
irr, respectively. There was significant interpatient variability
in the pharmacokinetic data (Table 1). Pharmacokinetic data
were similar for repeated weekly courses of idarubicin in the
two patients in whom pharmacokinetic studies were repeated
(data not shown). Idarubicinol was detected soon after parent
drug administration, and concentrations of idarubicinol were
greater than those of parent drug within 4-6 hours of drug
administration. Plasma elimination of the alcohol (r1/2, 56.8 h)
was greatly prolonged relative to that of parent drug (ti/ij, 17.6
h). Following daily administration of idarubicin, plasma con
centrations of idarubicinol were 5- to 10-fold greater than
parent drug during most of the 3-day treatment period. Idarub-
6526
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IDARUBICIN AND IDARUBICINOL
1,000.0
—
100.0
«
10.0
E
JS
°-
LO
0.2
24
48
72
96
Hours after first dose
Fig. 4. Plasma profile of idarubicin (O) and idarubicinol (•)following once
daily for 3 days every 3 weeks administration of 12.5 mg/m2idarubicin to patient
Dl.
, estimated concentrations for early time points following drug ad
ministration on days 1 and 2 based on data obtained on day 3.
PHARMACOKINETICS
of the weekly regimen were analyzed for idarubicin and idarub
icinol. Similar analyses were done with plasma obtained from
blood samples drawn at approximately the same time as the
CSF sample.
Idarubicin was detected in CSF from only 2 of 21 patients
from whom CSF samples were obtained during the study (Table
2). Both patients received idarubicin by the once daily for 3
days every 3 weeks treatment schedule. Idarubicinol was de
tected in 20 of the 21 patients as detailed in Table 2. Idarubi
cinol CSF concentrations varied over the range 0-1.05 ng/ml,
with a mean value of 0.51 ng/ml. On average, CSF concentra
tions of idarubicinol were 4% of metabolite concentrations in
plasma samples obtained at the same time. Insufficient CSF
samples were available from the 12.5 mg/m- dose to determine
the relationship between dose and idarubicinol CSF concentra
tion on the once weekly for 3 weeks schedules. For the once
daily for 3 days every 3 weeks schedule, the average (±SD)
idarubicinol CSF concentrations were 0.57 (0.29) and 0.70
(0.27) ng/ml for the 12.5- and 13.5-mg/m2 doses, respectively.
Table 1 Individual patient idarubicin pharmacokinetic data summary
Dose
Schedule
(mg/m2Weekly
Patient
herH (min)
h
DISCUSSION
Cl„
cinol:
(liters/m2)
(ml/min/m1,2491,5351.019135369580952556921975836998191.762166666664435625351,1721.492521100608031,1721.1691,0661,06116116279
*) '»
(h)89.528.5152.3141.859.882.652.844.721.951.222.648.244.926.853.627.458.377.048.920.939.356.835.7
We have characterized the plasma pharmacokinetics of ida
rubicin and the alcohol metabolite idarubicinol in children
receiving idarubicin as single agent therapy for relapsed leuke
mia. An important issue in such studies is the pharmacokinetic
12.11.7
behavior of the drug in pediatrie patients as compared to adult
9.63.2
patients. While it is always difficult to compare results from
17.48.31.913.52.9
widely divergent studies, data from this study and from pub
lished reports suggest that there are no major differences in
idarubicin and idarubicinol pharmacokinetics in children (17)
16.61.738.01.612.41.721.61.9
as compared to adults (18, 19). Our pediatrie data for 21
3"DlHH2DDlH6N2*F4ZIP4«GG216.410.412.06.53.49.36.618.917.017.734.27.75.712.112.828.546.011.111.58.712.713.0r7.72.7
10.0x312.513.515.0AverageSD)
patients were qualitatively similar to those of Tan et al. (17) for
7 patients. The terminal half-life value was somewhat prolonged
in our study when compared to their results (17.6 versus 11.3
h). Of equal importance is the age dependence of pharmacoki
15.04.0
netic parameters in pediatrie patients receiving equivalent doses
10.415.21.420.41.4
of the drug. In the limited number of patients studied, no
10.0x312.5Daily
16.12.1
2aG2°NIMl01CCIAlN4*N3HHlH
14.93.1
29.62.6
20.01.420.52.2
Table 2 Patient CSF and plasma concentrations of idarubicinol
17.71.2
13.30.9
PlasmaScheduleWeekly
14.42.1
17.6'0.8
6.8IdarubicinVd„
" Infusion data not available. A 15-min infusion was assumed.
* Plasma concentration-time data were fitted to a two-compartment
model.
' Average does not include values calculated using two-compartment
(mg/m2)
Patient10.0
x3Daily
tration
tration
(h)302424241824222122252424252424242220291824Concen
(ng/ml)6.388.997.547.8810.955.7311.989.511
(h)302424271830222124252424252624212220292
(ng/ml)0.560.650.471.050.140.140.290.35
ratios0.090.070.060.130.01
GlG2NlP2CCIMlN4AI12.5
open
open
model.
icin, and particularly idarubicinol, accumulated in plasma dur
ing the once daily for 3 days schedule (data not shown) as
predicted by the plasma elimination half-life values for parent
drug and metabolite. This is illustrated for one patient in Fig.
4. Mean 48-h urinary recoveries of idarubicin and idarubicinol
were 2.4 and 10.1%, respectively.
CSF Concentrations of Idarubicin and Idarubicinol. Based on
one published (16) and several anecdotal reports that idarubicin
was present in CSF following i.v. administration, we obtained
aliquots of CSF samples, drawn for clinical purposes, from
patients participating in this CCSG study. The aliquots ob
tained 18-30 h following idarubicin administration on the third
day of the daily for 3 days regimen or following the first dose
N3HHl12.5
.0315.3215.8325.6823.209.4015.8223.613.816.4615.5728.7230
1
X3DoseF2H5-Dl"HH2N2DDlH61
3.5
F4F3P4BlTime
' Idarubicin detected [0.14 (H5) and 1.57 (Dl) ng/ml] in these CSF samples.
6527
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IDARUBICIN AND IDARUB1CINOL PHARMACOKINETICS
relationship was found between the age of the patients and the
pharmacokinetic behavior of idarubicin and idarubicinol.
For both adult and pediatrie patients, plasma elimination of
idarubicin was characterized by a three-compartment
open
model, substantial exposure to the metabolite idarubicinol, and
much slower elimination of the alcohol when compared to
parent drug. The elimination half-life of idarubicinol may be
overestimated since the alcohol continues to be formed while
idarubicin is present in the body. This pattern of prolonged
alcohol elimination relative to parent drug elimination is similar
to that observed for anthracyclines, such as daunomycin (20),
and in contrast to anthracyclines, such as Adriamycin. Dauno
mycin has a greater affinity for aldo-keto reducÃ-asethan does
doxorubicin, and this may be the case for idarubicin as well. In
the latter case, the alcohol metabolite is eliminated at essentially
the same rate as parent drug, and plasma concentrations of the
alcohol are rarely greater than those of the parent drug (20).
The findings with regard to idarubicinol are important not
only as a mechanism of idarubicin elimination but also in light
of data concerning the cytotoxicity of idarubicinol and idarub
icin against tumor cells. Most side chain alcohol metabolites of
anthracycline-like agents are much less potent than the parent
drugs in terms of cytotoxicity against tumor cells in culture ( 10,
11). We found this to be true in studies with Adriamycin,
daunomycin, and epirubicin using human lymphoblastic and
myelogenous leukemia cells.4 In marked contrast, idarubicinol
was almost equitoxic with idarubicin in both cell lines (6).
These data suggest that idarubicin is an atypical anthracycline
anticancer agent in that patients are exposed to two very cytotoxic species rather than to an active parent drug and a much
less active major circulating alcohol metabolite.
Discussions of anthracycline pharmacology rarely note their
presence in the CNS following parenteral administration, and
they are not considered in the treatment of CNS disease. Our
analysis of CSF samples was based primarily on one report that
idarubicin was detected in CSF following i.v. administration to
an adult leukemia patient (16). It was particularly surprising to
detect idarubicinol in all but one patient given its greater
polarity compared to idarubicin.
It is difficult to predict the relationship between CSF and
plasma concentrations of idarubicin at times other than those
(18-30 h) for which we obtained samples. However, we would
predict that idarubicin would be detectable in CSF at earlier
time points following i.v. administration. More important,
based on plasma elimination data, we would predict that ida
rubicinol is present (most likely at higher concentrations) at
times earlier than 18-30 h and that levels may be sustained for
several days due to the slow plasma elimination half life (57 h).
We have preliminary data showing that exposures of 0.5-1.0
ng/ml idarubicinol for 3-5 days are cytotoxic to human leuke
mia cells in culture (6). Those exposure conditions may well
underestimate the CSF exposure in patients. Thus, the presence
of idarubicinol in CSF may warrant consideration in the treat
ment of diseases with CNS components.
4 M. J. Kuffel, J. M. Reid, and M. M. Ames, manuscript in preparation.
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Plasma Pharmacokinetics and Cerebrospinal Fluid
Concentrations of Idarubicin and Idarubicinol in Pediatric
Leukemia Patients: A Childrens Cancer Study Group Report
Joel M. Reid, Thomas W. Pendergrass, Mark D. Krailo, et al.
Cancer Res 1990;50:6525-6528.
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