Download Plasma Pharmacokinetics of Adriamycin and

[CANCER RESEARCH 43, 3417-3421,
July 1983]
Plasma Pharmacokinetics of Adriamycin and Adriamycinol: Implications
for the Design of in Vitro Experiments and Treatment Protocols
Raymond F. Greene, Jerry M. Collins,1 Jean F. Jenkins, James L. Speyer, and Charles E. Myers
Clinical Pharmacology Branch [R. F. G., J. M. C., J. F. J., J. L. S., C. E. M.], National Cancer Institute, and BiomédicalEngineering and Instrumentation Branch
[J. M. C.], Division of Ftesearch Services, NIH, Bethesda, Maryland 20205
ABSTRACT
tion (25). A physiological model of Adriamycin pharmacokinetics
based solely on flow limitation for tissue uptake and first-order
The plasma pharmacokinetics of Adriamycin and adriamycinol
following a 15-min infusion of 75 mg/sq m of Adriamycin were
studied in ten patients previously untreated with Adriamycin. The
disappearance kinetics of Adriamycin could adequately be de
scribed by a biexponential equation with an initial half-life of 8min and a terminal half-life of 30 hr. The major drug exposure
(area under the concentration-time curve) occurs during the
terminal phase where drug concentrations are generally less
than 10"7 M (0.05 ng/m\). An improvement in the high-perform
elimination by the liver has simulated the actual experimental
data in rabbits and humans reasonably well (9, 17). Compart-
ance liquid chromatography sensitivity facilitated the determina
tion of the terminal phase. The plasma kinetics of adriamycinol,
the major and only known active metabolite of Adriamycin, show
a rapid initial increase in plasma concentration followed by a
slow decline which parallels that of Adriamycin during the termi
nal phase. The relative drug exposure of adriamycinol to Adria
mycin was approximately 50%.
The relationship between the measured plasma drug levels
and free drug available for distribution into tissues was studied
by comparing the plasma binding characteristics of Adriamycin
and adriamycinol. A constant 20 to 25% of the total plasma
concentrations of both Adriamycin and adriamycinol was freely
diffusible over the whole range of observed concentrations, 20
nw to 2 MM. Thus, the free drug exposure (area under the
concentration-time curve) of tumor and host tissues in vivo can
be determined from these plasma measurements, since the free
drug exposures in plasma and in extracellular fluid are equivalent.
These results can also serve as a guide for the design of clinically
relevant in vitro studies of Adriamycin and adriamycinol.
The pharmacokinetic parameters determined in this study have
been used to simulate plasma concentration-time courses for a
variety of Adriamycin treatment schedules. Alternatives are sug
gested which reduce peak plasma Adriamycin concentration
while antitumor area under the concentration-time curve is main
tained.
INTRODUCTION
Adriamycin is an antitumor agent used in the standard chem
otherapy regimen of most hematological and many solid tumors
(8). Adriamycin is commonly administered clinically as a bolus
dose of 60 to 90 mg/sq m every 3 weeks (7). The plasma kinetics
of the drug following bolus administration exhibit a rapid initial
decline followed by a slow decline in plasma concentration which
has been ascribed to the ability of tissues to rapidly accumulate
the drug intracellularly followed by a slow release of the drug
from tissue stores as plasma levels decline due to drug elimina
1To whom requests for reprints should be addressed, at Building 10, Room
6N119, NIH, Bethesda, Md. 20205.
Received October 7, 1982; accepted April 11, 1983.
JULY 1983
mental modeling has also been used to describe the disposition
of Adriamycin in plasma. Initially, a biphasic loss of the drug was
proposed based on total fluorescence or radioactivity assay
methods (5, 12). The use of assay methods specific for Adria
mycin led to the inclusion of an intermediate phase showing a
triphasic loss of the drug (4, 6, 24), although no compelling
pharmacokinetic or pharmacodynamic justification for the third
phase has been proposed.
Although many studies of the plasma pharmacokinetics of
Adriamycin have been undertaken, certain deficiencies make the
interpretation of the pharmacokinetic data or its relevance to the
clinical use of Adriamycin difficult to understand: (a) The plasma
kinetics of Adriamycin have been fairly well studied for time
periods of up to 24 hr following a bolus injection; however, the
terminal half-life of Adriamycin is about 30 hr, which requires
sampling for several days for adequate characterization, (b)
Metabolism of Adriamycin requires assay techniques which sep
arate parent drug and metabolites and allow sensitive quantitation of Adriamycin and other metabolites of interest. The pres
ence of active metabolites can obscure the evaluation of either
the therapy or toxicity of the drug unless the activity of the
metabolite is evaluated. This general difficulty has been com
pounded in the case of Adriamycin, since much of the original
metabolite data was subsequently ascribed to artifacts from the
analytical methodology (23). (c) Although it is thought that only
free drug is available to produce drug effects, prior studies have
not quantitated the binding of either Adriamycin or adriamycinol
over the range of observed concentrations.
The primary purpose of this study is to provide a complete
description of the plasma pharmacokinetics of Adriamycin and
adriamycinol. The relevance of the pharmacokinetic parameters
to the in vivo and in vitro efficacy and toxicity of the drug is
discussed. Pharmacokinetic and pharmacodynamic principles
are applied to practical issues of Adriamycin scheduling and
cardiotoxicity.
MATERIALS AND METHODS
Clinical Characteristics. Ten patients undergoing single-agent Adri
amycin therapy for metastatic breast cancer, metastatic soft-tissue sar
coma, or nodular lymphomas, who had not been treated previously with
Adriamycin, were studied during their first course of Adriamycin therapy.
Adriamycin was administered at a dose of 75 mg/sq m through a fresh
i.v. infusion line over 15 min. As part of a study on cardioprotection,
2 The abbreviations used are: NAC, N-acetyl-L-cystelne; HPLC, high-perform
ance liquid chromatography; C x / or AUC, area under the concentration-time
curve.
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R. F. Greene et al.
some patients were randomly selected to receive 5.6 g/sq m of MAC2
from:
p.o. 1 hr before the dose of Adriamycin. All 10 patients had prior surgical
resections, but only one patient had prior chemotherapy (with strepto-
% of drug bound
zotocin). Liver function tests were within the normal range for all patients
at the time of study.
Sample Analysis. Blood samples were obtained at 0-, 0.08-, 0.17-,
0.5-, 1-, 3-, 6-, and then 24-hr increments following administration of the
drug for at least 3 days. Blood samples were generally collected from a
vein on the opposite arm from the infusion. If necessary, samples were
taken from the same vein used for infusion, after extensive flushing. No
major differences were observed between patients sampled by the 2
methods. The most likely error would be an overestimate in the early
samples. Since most of the drug exposure is in the later phases, such
an error would not be critical.
The blood was collected in glass tubes containing EDTA and were
immediately placed on ice to prevent metabolism by the cellular blood
components. The blood was centrifugea at 600 x g for 10 min to obtain
plasma which was frozen at -40° until analyzed.
Each plasma sample was analyzed for Adriamycin and adriamycinol
by means of a HPLC with fluorescent detection capable of separating
and yielding sensitive and specific quantitation of each compound. Sam
ples were prepared for analysis by adding 1 ml of 0.1 M sodium borate
buffer (pH 9.8) and 50 ng daunomycin as an internal standard to 1 ml of
the plasma sample and extracting the drug into 17 ml of chloroforrrrmethanol (4:1, v/v) in a 50-ml glass tube. The organic layer was
transferred to a conical glass tube and evaporated to dryness under
nitrogen at room temperature. The residue was redissolved in 150 ^l
methanol, and an aliquot was injected into the HPLC. Exposure of the
samples to light was limited as much as possible. Standards containing
Adriamycin (0 to 200 ng/ml), adriamycinol, and Adriamycin aglycone in
plasma were processed in an identical fashion and used for quantitation.
The HPLC system used was essentially the reverse-phase system
described by Israel et al. (18) with one modification. An excitation
wavelength of 228 nm rather than 482 nm was used which yielded an
approximately 10-fold increase in sensitivity for each compound. No
evidence of interfering fluorescent peaks was observed in "pre-" dose
samples.
Quantitation of drug concentrations was achieved by measuring the
peak height ratios of drug:internal standard for the plasma standards
and obtaining a least-squares fit of peak height versus concentration.
The concentrations of Adriamycin and adriamycinol in the plasma sam
ples were then obtained from the peak height ratios of the samples.
The recovery of Adriamycin, adriamycinol, and the internal standard
in the assay procedure was approximately 70% within the concentration
range of the standards. The detection limit of the assay (signal of 5 times
the average noise) was experimentally determined to be 2 nw for Adria
mycin and adriamycinol using 1 ml of plasma. The within-day precision
(C.V.) of the assay (n = 5) at 1 pM was 7.1% for Adriamycin and 8.2%
for adriamycinol; at 10 nw, it was 11.2% for Adriamycin and 18.6% for'
adriamycinol.
Plasma Binding of Adriamycin and Adriamycinol. Plasma was used
immediately after it was obtained from either normal volunteers or
patients on this pharmacokinetic study, before or after treatment with
NAC and/or Adriamycin. Plasma (1.2 ml) was spiked with Adriamycin
and adriamycinol and added to one side of a commercial dialysis cell
(Technilab Instruments, Pequannock, N. J.). An equal volume of phos
phate or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic
acid buffer (0.1
M. pH 7.4) was added to the other side. Dialysis was performed at 37°
in the dark, with gentle shaking. Preliminary studies showed that equilib
rium was achieved between 12 and 20 hr and that the equilibrium pH
was 7.4 in both plasma and buffer. The HPLC assay was used to
determine the concentrations of Adriamycin and Adriamycinol in the
plasma and buffer. [uC]Adriamycin was also used for binding experi
ments after prepurification by HPLC. No decomposition of Adriamycin or
adriamycinol was evident when dialysis times of less than 20 hr were
used. The percentage of drug bound to plasma proteins was calculated
3418
(Plasma concentration
—buffer concentration)
Plasma concentration
Pharmacokinetic
Analysis. The Adriamycin plasma concentration-time
data were fitted to a biexponential equation:
Cp(f) = A exp(-«f) + B exp(-/fl)
(B)
where Cp(f) is the drug concentration at time, f, after an i.v. dose of the
drug. A and B are constants, and «and ßare the apparent first-order
elimination rate constants. The data fits were performed on MLAB, a
nonlinear fitting program, using a 1/concentration squared weighting
function (20). The areas under the curve (C x f ) of the initial and terminal
phases for Adriamycin were calculated from the ratios of A/a and B/ß.
The total AUC for Adriamycin and adriamycinol were also calculated
based on the trapezoidal rule from zero to the last measured time point
and then by first-order extrapolation to infinite time using the experimen
tally determined half-life value for Adriamycin. The extrapolation averaged
14% of the total area for Adriamycin and 20% for adriamycinol. The
percentage of drug exposure of adriamycinol in relation to Adriamycin
was calculated from the ratio of the total AUC of adriamycinol to AUC of
Adriamycin.
The volume of distribution (V„)and total body clearance (ClrB) for
Adriamycin were calculated by means of noncompartmental techniques:
Dose
(C)
AUC
Steady-state
VK =
(Dose) (AUMC)
AUC2
(D)
where the area under the moment curve (AUMC) was calculated using a
published method (3).
RESULTS
Pharmacological Studies. Following the 15-min infusion of
Adriamycin, the Adriamycin plasma concentration exhibited an
initial rapid decline from approximately 5 to 0.1 ^M within 1 hr.
This initial phase was followed by a slower decrease ¡nconcen
tration which was fairly log-linear beyond 6 hr (Chart 1). A rapid
IUWV1000/—
(¿)_
Adriamycin
2Adriamycinol
(O)\
(n=10)^M\ATe<
2
SZ
Mean ±SD
C
•^rf'o
10°"5C"e
" "~T - - ^f~~~^"^^~-2J_
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10o
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1AJ
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iiii0
24
96TIME48
(hours)
72
Chart 1. Measured Adriamycin and adriamycinol plasma concentration-time
terns following a 15-min infusion of Adriamycin 75 mg/sq m to 10 patients.
CANCER
RESEARCH
pat
VOL. 43
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Clinical Pharmacokinetics of Adriamycin
Table 1
Pharmacokinetic parameters obtained from biexponential analysis of Adriamycin plasma concentration-time
Initial phase
A (MM)
Adriamycin alone* (n = 5)
3880 ±1078*
Adriamycin + NAC (n = 5)
4970 ±2236
tin (min)
10.0 ±2.2
6.9 ±1.1
profile
Terminal phase
Cxi (nM-hr)
B (nu)
933(21.7%)
77.2 ±10.5
f,/2 (hr)
C x t (nw-hr)
30.2 ±1.9 3364(78.3%)
830(19.5%)
24.6 ±2.7
96.8 ±11.1
3436(80.5%)
Combined groups (n = 10) 4425 ± 678
8.5 ±1.3 882(20.6%)
87.0 ± 7.9 27.4 + 1.8 3400(79%)
8 There was no significant difference (p > 0.2) in any parameter between groups given Adriamycin alone or Adriamycin
plus NAC.
6«
Mean ±S.E.
increase ¡nadriamycin plasma concentration was observed in
the first hr followed by a decline in concentration which generally
paralleled that of Adriamycin. At the retention time for Adriamycin
aglycone, only small fluorescent peaks were observed corre
sponding to concentrations of generally less than 10 nw (based
on the aglycone standard).
The concentration-time data for Adriamycin for each patient
were analyzed separately as described in "Materials and Meth
ods" to obtain estimates of the pharmacokinetic parameters.
Table 1 shows the relative contribution of each phase to the
total AUC (C x f) and the estimates obtained for Adriamycin
when the data were grouped by treatment category (Adriamycin
alone versus Adriamycin plus NAC). No significant differences in
the values of each group were evident. Using the data from all
the patients studied, the pharmacokinetics of Adriamycin could
best be fit to a biexponential equation of the form:
Table 2
Noncompartmental values for the clearance (Cira) and steady-state distribution
volume (V„)
of Adriamycin and plasma drug exposure (C x T) of Adriamycin and
Adriamycinol
Adriamycin alone
jg (mi/min/
sqm)
514 ±56C
Adriamycin + MAC*
494 + 50
Adriamycin
C x f*
Adriamycinol
C x fa
V«(liter/kg)
28.0 ±3.3
(nM-hr)
4427 ±418
(nu-hr)
2137 ±472
22.4 ±4.4
4516 + 413
2422 + 565
504 + 35
25.2 ±2.7
4477 ±277
2280 + 350
Combined groups
a Total drug plasma C x t. For both Adriamycin and Adriamycinol, multiply total
by 0.25 to obtain free drug Cxi.
6 There was no significant difference (p > 0.2) in any parameter between groups
given Adriamycin alone or Adriamycin plus NAC.
c Mean ±S.D.
drug exposure is directly proportional to the total drug exposure
in plasma; and (c) the free drug exposure of adriamycinol is
approximately one-half of that for Adriamycin.
Cf(t) = 4147 exfX-5.39 f) + 82 exp(-0.0229 f)
A biexponential model for Adriamycin appears to be sufficient
where Cp(t) is the nw Adriamycin concentration, and time, f, is ¡n to describe the major features of both the pharmacokinetic profile
and the pharmacological activity of Adriamycin. The initial phase
hr.
Table 2 shows the total body clearance and steady-state
consists of a very rapid decline in plasma Adriamycin concentra
tions. Initial concentrations are 50-fold higher than those ob
volume of distribution of Adriamycin and the AUC of adriamycinol
and Adriamycin for the 2 groups. Similar values were obtained;
served at the start of the terminal phase. Despite the relative
magnitude of the concentrations observed during the initial
thus, the plasma pharmacokinetics of Adriamycin and adriamy
cinol appear to be unaffected by administration of NAC. The Vss phase, the terminal phase provides 75% of the total drug expo
of 25 liters/kg compares favorably with the tissue: plasma parti
sure and maintains cytotoxic concentrations for several days,
tion coefficients determined in a rabbit study (17).
since the fi/2 is 30 hr. The biphasic curve can be used to examine
Binding Studies. For nonradioactive drug (n = 12), Adriamycin the 2 patterns of Adriamycin therapeutic and toxic effects which
was 74 ±1.7% (S.D.) bound, and adriamycinol was 76 ±1.4%
have been observed: those due to high peak concentrations,
bound. The percentage bound was independent of plasma con
and those related to total drug exposure.
centration over the range observed in this study, 20 nM to 2 U.M.
In addition to its own pharmacological activity, Adriamycin is
also metabolized to one known active metabolite, adriamycinol.
There was no difference in Adriamycin binding for plasma sam
The plasma kinetics of both compounds were determined in an
ples from patients receiving NAC versus patients not receiving
attempt to determine the relative importance of these 2 chemical
NAC.
At 1 (¿M,
the [14C]adriamycin was found to be 82 ±0.7%
species to the pharmacological activity observed after Adriamy
bound by radioactivity measurements and 75 ±2.7% bound by cin administration. These studies showed a relative drug expo
sure for total plasma adriamycinol of approximately one-half of
the HPLC method. More than 95% of the total radioactivity
initially present was recoverable in the plasma and buffer solu
the value for total Adriamycin. Since equivalent plasma binding
was found for Adriamycin and adriamycinol, the free drug expo
tions at equilibrium. For both radioactive and nonradioactive
studies, binding of the drug to the dialysis apparatus was cor
sure ratio is the same as for total drug exposure. Studies of the
rected for by sampling both the plasma and buffer sides of the relative cytotoxicity of Adriamycin and adriamycinol have shown
dialysis membrane.
that adriamycinol is less active than Adriamycin (22), at least for
1-hr exposures. Presumably, these short-term results are also
applicable
to longer exposures since, as discussed below, cy
DISCUSSION
totoxicity of Adriamycin is not directly time dependent (16). Thus,
for patients with normal hepatic function, Adriamycin appears to
The major conclusions drawn from the analysis of the phar
be the principal species responsible for therapeutic effect. The
macokinetic data for Adriamycin are: (a) the bulk of the drug
role of adriamycinol may be more important in patients with liver
exposure (C x T) occurs during the terminal phase: (b) the free
JULY 1983
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R. F. Greene et al.
:,A>Jli;
do«9
lor 7S mo/m2
total
Slmulollon.
B
InluilonSlnota
Doy Conltnuou.
for 75 mfl/m
teto! dOM
5-t>oy Coflttnuoua Infutlon
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Ion—
1000
15 Ulnut.
Int u.
Slngi*
Infuclon q?4*i x S
15-M1fiut« Infuilon
1000:
\•?
\;
Chart 2. Simulated Adriamycin concentra
tion-time patterns for a total dose of 75 mg/sq
m administered by various schedules. A, shortterm (0 to 5 hr) patterns; B, long-term (up to
120 hr) patterns. q24h x 5, every 24 hr for 5
days.
;
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TIME (hours)
disease, since it has been reported that total adriamycinol plasma
concentrations are higher than total Adriamycin plasma concen
trations (10). Also, the importance of daunomycinol in the ther
apeutic efficacy of daunomycin may be substantially different,
since daunomycin is metabolized to the alcohol metabolite to a
much greater extent resulting in daunomycinol plasma exposure
much greater than that of daunomycin (2).
The major purpose of this study has been to obtain an accurate
and complete concentration-time profile of free Adriamycin and
adriamycinol in plasma. Since the plasma binding of both Adria
mycin and adriamycinol is constant over the observed range of
plasma concentrations, the free drug concentration-time profile
represents 20 to 25% of the total drug profile of Chart 1. The
pharmacological activity of a drug is generally determined by the
free drug. These plasma free-drug exposure measurements are
directly applicable to both tumor and host tissue free-drug ex
posure in vivo, i.e., for tissues which do not have substantial
clearance of the drug, normal and tumor cells will be exposed to
extracellular free-drug concentrations that are identical to plasma
free-drug exposure.
The design of in vitro experiments should also be guided by
these principles. Since cells in vitro are exposed to drug via a
medium which substitutes for extracellular fluid, it should be
possible to evaluate the pharmacodynamic activity of Adriamycin
in vitro under conditions which would yield the same free-drug
exposure observed in vivo. None of the in vitro cell survival
studies to date has considered the activity of the anticancer drug
in relation to its free-drug concentration. These studies have
included fetal calf serum in varying amounts in the incubation
medium. The binding characteristics of Adriamycin in these prep
arations are not known but should be investigated if the ultimate
purpose for such studies is to make comparisons with clinically
achievable exposures. Such an approach may provide better
predictive capabilities than does the present standard method,
which routinely uses an exposure of one-tenth of the peak total
plasma concentration for 1 hr (1).
There is a log-linear relationship for Adriamycin between the
surviving fraction of tumor cells and concentration or exposure
duration within the therapeutic range (13, 14). This relationship
is typical of phase nonspecific agents (19):
log S, = -k(C x f)
where S, is the surviving cell fraction (A//A/0),and k is a propor
tionality constant relating the C x T pattern to cell survival. The
correlation of survival fraction with both concentration and time
48
72
96
120
TIME (hours)
for Adriamycin has recently been studied under conditions rele
vant to Adriamycin pharmacology (16). Exposure of human colon
tumor cells to Adriamycin concentrations of 10, 100, and 1000
nM for either 2 or 24 hr demonstrated a good correlation between
the C x T value and the log of the surviving fraction.
The observed correlation of in vitro tumor cell survival and C
x T suggests that the antitumor effects of Adriamycin are dose
dependent, but schedule independent. Clinical studies of the
antitumor effects of Adriamycin have supported this conclusion.
It has been reported that Adriamycin is equally effective regard
less of the administration schedule used, namely, weekly or
triweekly bolus or continuous infusion (11,21 ).
The importance of dose and schedule should also be viewed
from the perspective of limitations imposed by host tissue toxicity. Both cardiotoxicity and drug-induced emesis have been
reported to be schedule-dependent and may be more associated
with the peak drug concentrations than with total drug exposure.
These latter side effects have been lessened by an infusion
rather than as a bolus, without any concomitant changes in the
tumor efficacy or bone marrow depression (21 ). Earlier studies
(8) suggest that bone marrow depression may be schedule
dependent.
Even this limited information about Adriamycin pharmacodynamics can permit the more effective use of pharmacokinetics
towards a goal of optimal chemotherapy. Although the 2- to 5day continuous infusion schedule may be superior to bolus
administration with respect to cardiotoxicity, it possesses draw
backs in terms of practical implementation, especially in the
setting of a large outpatient practice. The need for central venous
catheter placement, a pump, and additional patient monitoring
would make routine use of these protocols difficult.
One practical application of pharmacokinetics is to predict
concentration-time profiles for alternate dosing strategies. Using
the pharmacokinetic data from Table 1 and standard formulas
for schedule adjustment (15), we have explored a variety of
delivery options and summarized the results in Chart 2. Dividing
a single large dose into several smaller doses is one method of
reducing peak concentrations. For example, the peak plasma
Adriamycin concentration can be reduced 5-fold by simply split
ting the single 75 mg/sq m dose into 5 daily doses of 15 mg/sq
m.
Lengthening the infusion time also lowers the peak plasma
concentration. The peak concentration observed after a 15-min
infusion, such as that used in this study, is already 40% lower
than the peak concentration predicted for a 15-sec rapid i.v.
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Clinical Pharmacokinetics of Adriamydn
push. An additional 6-fold reduction in peak concentration can
be achieved by lengthening the infusion time from 15 min to 2
hr, which could still be administered peripherally. The combina
tion of dividing the single dose into 5 daily doses and prolonging
each infusion from 15 to 120 min provides an alternate schedule
which produces a peak concentration 30-fold lower than that
observed in the current study.
No simple combination of divided doses and constant infusions
actually produces a constant plasma concentration. For the
alternate schedule, there is some daily increase and decrease in
concentration, while the continuous infusion protocol only
reaches steady state by the end of a 120-hr period. Both the
intermittent 2-hr schedule and the 120-hr continuous infusion
schedule provide comparable concentrations for most of the 5day period. For a 48-hr infusion, which has also been tested (21),
the simulated plasma concentration rises throughout the infusion
period. This behavior is expected for a drug with a controlling
f1/2 of 30 hr. Whether this alternate schedule can reduce the
incidence of cardiotoxic side effects to a level achievable by 2to 5-day constant infusions will have to be experimentally verified.
The scheme, however, illustrates the value of pharmacokinetics
as a tool which can be used to assist in the search for optimal
delivery methods.
ACKNOWLEDGMENTS
We thank Dr. Ian Kerr and Dr. Luca Gianni for helpful discussions and Raymond
Klecker for analytical assistance.
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3421
Plasma Pharmacokinetics of Adriamycin and Adriamycinol:
Implications for the Design of in Vitro Experiments and
Treatment Protocols
Raymond F. Greene, Jerry M. Collins, Jean F. Jenkins, et al.
Cancer Res 1983;43:3417-3421.
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Downloaded from cancerres.aacrjournals.org on April 29, 2017. © 1983 American Association for Cancer Research.