PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS Clin Pharmacokinet 2002; 41 (6): 431-444

0312-5963/02/0006-0431/$25.00/0

© Adis International Limited. All rights reserved.

Pharmacokinetic-Pharmacodynamic
Relationships of the Anthracycline
Anticancer Drugs
Romano Danesi,1 Stefano Fogli,1 Alessandra Gennari,2 Pierfranco Conte2 and
Mario Del Tacca1
1 Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and
Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
2 Division of Medical Oncology, University Hospital, Pisa, Italy

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
1. Clinical Pharmacology of Anthracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
1.1 Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
1.2 Epirubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
1.3 Idarubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
1.4 Anthracycline Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
1.5 Anthracycline Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
1.6 New Anthracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
2. Biological Basis of Pharmacokinetic-Pharmacodynamic Modelling . . . . . . . . . . . . . . . . . 439
3. Theoretical Basis of Pharmacokinetic-Pharmacodynamic Modelling . . . . . . . . . . . . . . . . . 440
4. Clinical Application of Pharmacokinetic-Pharmacodynamic Relationship . . . . . . . . . . . . . 441
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

Abstract The anthracycline glycoside antibiotics represent a group of potent anticancer

agents with a wide spectrum of activity against solid tumours and haematological
malignancies, and are the mainstay of a large number of clinical protocols for the
treatment of adult and childhood neoplastic diseases. Their clinical activity is
limited, however, by acute and chronic adverse effects. Myelosuppression, pre-
dominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition
to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepato-
pathy, characterised by elevated bilirubin concentrations, occurs less frequently.
Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can
be acute or chronic; in the acute setting, electrocardiographic abnormalities may
be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity
represents a serious adverse effect that may be lethal due to the development of
irreversible, cumulative dose–dependent, congestive cardiomyopathy.
The occurrence of toxicity displays a marked interindividual variation, and
for this reason the pharmacokinetics and pharmacodynamics of anthracyclines
have been extensively investigated in order to identify integrated models that can
be used in the clinical setting to prevent the development of serious toxicity,
432 Danesi et al.

mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been

recognised to influence both the toxicity and the activity of anthracyclines; in
particular, there is increasing evidence that the mode of administration plays an
important role for cumulative cardiotoxicity and data indicate that bolus admin-
istration, rather than continuous infusion, appears to be an important risk factor
for anthracycline-induced cardiomyopathy, thus implying that this type of toxic-
ity is maximum concentration-dependent. On the contrary, exposure to the drug,
as measured by area under the curve, seems best related to the occurrence of
leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic
models allows the simulation of drug effects and ultimately dose optimisation in
order to anticipate important toxicities and prevent their occurrence by the ad-
ministration of prophylactic treatments.

The importance of pharmacokinetic-pharmaco- of drug dosages and schedules to maximise thera-

dynamic (PK-PD) modelling in drug development
is becoming increasingly recognised. In preclinical
studies, PK-PD is used to support drug discovery,
interpret toxicokinetic experiments and, by the use
of physiological modelling, to extrapolate from ani-
mal models to humans. In the clinical programme,
PK-PD is used to support dose-finding and dose-
escalation studies, and more recent applications in-
clude concentration-controlled clinical trials and
population PK-PD. For drugs such as anticancer
agents with a very narrow therapeutic index, the
minimisation of interpatient variability in drug ex-
posure allows the maximisation of the benefit,
while keeping the risk of serious adverse effects to
an acceptable level, and this strategy is particularly
important when the treatment is given with cura-
tive intent.[1]
Pharmacokinetic models are currently used in
phase I clinical trials to characterise drug distribu-
tion and elimination; in addition to this, special
attention is devoted to drug effects, as described by
a pharmacodynamic approach, since the clinical
and therapeutic value of a drug depends upon its
dynamic effect. Several factors may limit the use
of this approach for cancer chemotherapeutic
agents, including poorly defined concentration-
effect relationships, heterogeneous biological be-
haviour of cancer and individual variability in the
toxic effects of anticancer agents. However, the
measurement and interpretation of drug concentra-
tions in biological fluids and the individualisation
peutic effects and minimise toxicities have been
addressed in a number of pharmacodynamic stud-
ies to establish a relationship between serum con-
centrations and dose-limiting toxicities for anti-
cancer agents, including anthracyclines.[2]
The anthracycline antibiotics were introduced
into clinical practice more than 20 years ago, and
since then they have been characterised by wide-
spread clinical use that makes them one of the most
successful drug categories. The anthracycline an-
tibiotics comprise a group of cytotoxic compounds
with wide-ranging activity against human malig-
nancies. They are used extensively for curative,
adjuvant and palliative therapy, both as single
agents and in combination regimens. The anthra-
cyclines produce a number of adverse effects; how-
ever, the most important of them is cardiotoxicity.
Although clinically significant cardiac damage
may be caused by the administration of other
agents, including mitoxantrone, fluorouracil, al-
kylating agents and amsacrine, the frequency and
severity observed with anthracyclines justify spe-
cial attention to this problem. Strategies have been
devised to circumvent this adverse effect, includ-
ing development of less toxic analogues, alter-
ations in scheduling, administration of cardio-
protective agents and advanced methods for
monitoring cardiac abnormalities.[3]
The profile of drug activity and pharmacokinetics
may be further modulated by the coadministration
of a number of drugs, including chemotherapeutic

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (6)
Pharmacokinetics-Pharmacodynamics of the Anthracyclines
agents (taxanes, alkylating agents, antimetabolites
and monoclonal anti-CD20 and anti-HER2/neu
antibodies), multidrug-resistance reverting agents
(verapamil, cyclosporin, valspodar) and cardio-
protective drugs, such as dexrazoxane (ICRF-
187), that are able to affect drug disposition, me-
tabolism and pharmacodynamics. In particular,
taxanes and the excipient Cremophor EL interact
with the P-glycoprotein transport system of anthra-
cyclines at the biliary level and strongly influence
the disposition of doxorubicin and epirubicin as
well as their metabolites, with enhanced myelo-
toxicity and stomatitis,[4,5] whereas trastuzumab, a
monoclonal antibody against the product of the
HER2/neu oncogene for the treatment of breast
cancer, enhances the cardiotoxic effect of anthra-
cyclines.[6] Finally, the entrapment of anthracy-
clines in lipid carriers (pegylated liposomal doxo-
rubicin or liposomal daunorubicin) is associated
with a substantial change in clinical activity and
toxicity, mostly dependent on changes in pharma-
cokinetic profile with respect to the parent drugs.[7]
Most anthracyclines, including epirubicin and
idarubicin, have a predictable correlation between
dose and pharmacokinetics, particularly area un-
der the concentration-time curve (AUC), and this
feature facilitates dose adjustment with the adop-
tion of simple algorithms. In other instances, how-
ever, more complex approaches are required to
predict erratic pharmacokinetic behaviour.
The aim of this article is to review the theoret-
ical and clinical bases of the relationship between
drug distribution and effects of anthracycline anti-
tumour drugs, in order to find clinically useful
guidelines for improved drug use in cancer pa-
tients. A specific section on the clinical relevance
of the issues examined is included at the end of the
manuscript, and the implications of the PK-PD ap-
proach to treatment optimisation are underscored.
The present paper reviews the scientific literature
indexed in the MEDLINE database on the issues
of PK-PD relationships, with particular focus on
clinical pharmacology and oncology applications
in which a detailed analysis of drug distribution
and effects is reported.
© Adis International Limited. All rights reserved.
433
1. Clinical Pharmacology
of Anthracyclines
Several anthracyclines have reached the level
of clinical development and are represented in fig-
ure 1, while table I summarises the relevant phar-
macokinetic and pharmacodynamic characteris-
tics and PK-PD relationships. Doxorubicin and
daunorubicin represent first generation anthracy-
clines, and epirubicin and idarubicin are second
generation compounds. Doxorubicin is a deriva-
tive of daunorubicin (14-hydroxy-daunorubicin)
and is an essential component of the treatment of
aggressive lymphoma, childhood solid tumours,
bone and soft tissue sarcomas, as well as breast
cancer. Epirubicin has a spectrum of activity very
similar to that of doxorubicin but with lower tox-
icity. On the other hand, daunorubicin has occu-
pied the central position of interest in the treatment
of acute lymphocytic leukaemia, whereas idaru-
bicin is an effective agent for the management of
acute myeloblastic leukaemia and is reportedly
more potent and less cardiotoxic than dauno-
rubicin or doxorubicin. Anthracyclines with less
extensive clinical development include iododoxo-
rubicin[8,9] and methoxymorpholino-doxorubicin
(nemorubicin, PNU-152243).[10] Finally, prodrugs
of doxorubicin have also been developed, includ-
ing N-L-leucyl-doxorubicin,[11] pirarubicin (4′-O-
tetrahydropyranyl-doxorubicin)[12] and valrubicin
(N-trifluoroacetyl-doxorubicin-14-valerate, AD-
32),[13,14] as well as novel delivery systems, includ-
ing polymer conjugates[15] and liposomal carri-
ers.[16] The improved tolerability profile of
anthracycline prodrugs and of delivery systems is
a consequence of the slow release of daunorubicin
or doxorubicin, and their PK-PD relationships are
dependent on the distribution parameters of the ac-
tive drugs. The ability of dexrazoxane to protect
against anthracycline cardiotoxicity further en-
hances clinical interest in exploiting dose intensity
modifications to therapeutic advantage.[17] New
areas of research in relation to anthracycline anti-
biotics include the introduction of novel analogues
with improved DNA-binding properties, the rever-
Clin Pharmacokinet 2002; 41 (6)
434 Danesi et al.

O OH O O OH O

C CH2 OH C CH3

OH OH

CH3O O OH O CH 3O O OH O

H3C O H 3C O

NH2 NH 2
HO HO
Doxorubicin Daunorubicin

O OH O O OH O

C CH3 C CH2 OH

OH OH

H O OH CH3O O OH

O O

H3C O H3C O

HO
NH2 NH2
HO
Idarubicin Epirubicin

O OH O O OH O

C CH2 OH C CH2 OH

OH OH

CH3O O OH CH3O O OH O

O
H3C O

H3C O NH2
O

NH2 O
I
4'-lodo-doxorubicin Pirarubicin

Fig. 1. Chemical structures of selected anthracyclines for human use.

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (6)
 Table I. Summary of pharmacokinetic-pharmacodynamic relationships of representative anthracyclines in human use

Anthracycline Cytotoxic metabolites PK-PD relationship Dose-limiting toxicity References

PK parameter PD parameter

Doxorubicin (DXR) Doxorubicinol (DXR-ol) AUCDXR Leucocytes, platelets Bone marrow 18-20

AUCDXR-ol PMN, platelets

Epirubicin (EPI) Epirubicinol (EPI-ol) AUCEPI, AUCEPI + EPI-ol Stomatitis Bone marrow 21-24

Cmax,EPI, C2,EPI, t1⁄2,EPI Stomatitis

AUCEPI, AUCEPI + EPI-ol PMN, leucocytes

© Adis International Limited. All rights reserved.

AUMCEPI, Cssp,EPI Leucocytes (AOC)

Idarubicin (IDA)a Idarubicinol (IDA-ol) AUCIDA, AUCIDA-ol PMN Bone marrow 25

Cmax,IDA, Cmax,IDA-ol PMN

Iododoxorubicin (I-DXR) Iododoxorubicinol (I-DXR-ol) AUCI-DXR PMN, platelets Bone marrow 8,9

AUCI-DXR + I-DXR-ol PMN, platelets

Pharmacokinetics-Pharmacodynamics of the Anthracyclines

MEN-10755 N/A N/A N/A Bone marrow 26

Methoxymorpholino-doxorubicin Methoxymorpholino- None None Bone marrow 10

doxorubicinol

Anthracycline prodrugs and delivery systems

Pirarubicin DXR, DXR-ol AUCDXR Leucocytes Bone marrow 12

N-L-leucyl-doxorubicin DXR, DXR-ol AUCDXR Leucocytes, PMN Bone marrow 11,27

Valrubicin (AD-32) DXR, DXR-ol AUCDXR Leucocytes Bone marrow 13,14

Pegylated liposomal doxorubicin DXR-ol Cmax,DXR Stomatitis, leucocyte nadir Stomatitis 28

t1⁄2,DXR Palmar-plantar Skin toxicity

erythrodysaesthesia

a Oral treatment.
AOC = area of neutrophil-time curve (AOC) below 4000 cells/μl; AUC = area under the plasma-concentration-time curve; AUMC = first moment AUC; Cmax = peak plasma concentration;
C2 = plasma concentration at 2h post-dose; Cssp = plasma concentration at steady state; N/A = not available; None = no PK-PD demonstrated; PK-PD = pharmacokinetic-pharma-
codynamic relationship; PMN = polymorphonuclear neutrophils; t1⁄2 = terminal half-life.

Clin Pharmacokinet 2002; 41 (6)

435
436
sal of multidrug resistance and the rational devel-
opment of drug combinations.
1.1 Doxorubicin
Doxorubicin displays linear pharmacokinetics
after intravenous administration, is widely distrib-
uted in the plasma and tissues, with a volume of
distribution (Vd) exceeding 500 L/m2, and has a
plasma protein binding ranging from 50 to 85%.
The drug is extensively metabolised in the liver by
aldo-keto reductase, to yield the dihydrodiol deriv-
ative doxorubicinol, which retains antitumour ac-
tivity, and by the NADPH-dependent cytochrome
P450 (CYP) reductase to cleave the glycosidic
bond and release aglycone metabolites that are in-
volved in the development of cardiotoxicity.
Doxorubicin undergoes a triphasic plasma decay,
with an initial half life (t1⁄2α) of 4.8 min, a t1⁄2β of 2.6
hours and a terminal t1⁄2γ of about 48 hours.[29] Renal
clearance of doxorubicin is low, and about 12% of
total dose is recovered in the urine during 6 days
after treatment; however, hepatic clearance is high,
with more than 50% of the drug excreted in the bile
within 7 days after treatment. Therefore, biliary
elimination and faecal excretion of the parent com-
pound and its metabolites are of major clinical rel-
evance. About 10 to 20% and 40 to 50% of the dose
is excreted in faeces within 24 and 150 hours, re-
spectively. About 50% of the biliary eliminated
dose is unchanged drug, 23% is doxorubicinol and
the remainder consists of other metabolites.[29]
Due to the important role of hepatic metabolism
and biliary excretion in the clinical pharmacokinet-
ics of anthracyclines, patients with liver dysfunc-
tion, as evidenced by hyperbilirubinaemia and/or
elevated liver enzymes, may show significant ab-
normalities in drug distribution parameters.[30,31]
A widely agreed clinical practice, although
based on empirical considerations, recommends
the administration of 50% of the planned dose of
epirubicin, doxorubicin or daunorubicin if serum
total bilirubin and AST (SGOT) concentrations
range from 25.65 to 51.3 μmol/L and 60 to 180
U/L, respectively. If serum bilirubin ranges from
53.01 to 85.5 μmol/L and AST levels exceed 180
© Adis International Limited. All rights reserved.
Danesi et al.
U/L, only 25% of the planned dose should be ad-
ministered; if serum bilirubin concentrations ex-
ceed 85.5 μmol/L, doxorubicin, epirubicin and
daunorubicin are contraindicated.[29] In patients
with mild hepatic function abnormalities and se-
rum bilirubin less than 25.65 μmol/L and AST con-
centrations less than 60 U/L, drug doses should not
be reduced, because there is some evidence that
lower peak plasma concentrations (Cmax) may
yield a shorter duration of response and sur-
vival.[29,32]
Investigation of PK-PD correlation, by linear or
sigmoidal maximum-effect (Emax) modelling, re-
vealed significant relationships between the AUC
of doxorubicin and leucocyte (r = –0.69, p = 0.006)
and platelet (r = –0.71, p = 0.004) counts,[18] as well
as between the AUC of doxorubicinol and the de-
crease in neutrophils and platelets (p < 0.02),[19]
respectively. In patients with small cell lung cancer
given combination treatment with cyclophosph-
amide and vincristine, a significant relationship
was found between the AUC of doxorubicin and
leucocyte counts (table I), whereas no correlations
were noted between the AUC of doxorubicinol and
thrombocytopenia or neutropenia.[20]
Doxorubicin-induced cardiomyopathy may be
significantly reduced by prolongation of intrave-
nous infusion. A clinical study in children treated
with doxorubicin 60 mg/m2 over 24 hours and 75
mg/m2 over 72 hours showed a reduced incidence
of congestive heart failure (1/97 patients) com-
pared with a conventional bolus schedule (13% of
patients with congestive heart failure). No substan-
tial differences were noted in the tumour response
between continuous infusion and bolus administra-
tion.[33] This evidence indicates that Cmax, rather
than AUC, is related to the development of chronic
cardiotoxicity. However, a prolonged infusion
time increases the incidence and severity of
mucositis and bone marrow suppression, which
then become the dose-limiting toxicities.[29] The
plethora of studies under way reflects the current
dilemma on the optimal dose and schedule of an-
thracyclines, and it has not yet been precisely es-
tablished which infusion schedule may result in op-
Clin Pharmacokinet 2002; 41 (6)
Pharmacokinetics-Pharmacodynamics of the Anthracyclines
timal effectiveness of therapy. There is some evi-
dence that the volume of distribution at steady state
(Vss) is higher after prolonged administration than
after conventional short intravenous injection.
Thus, it has been suggested that the prolongation
of infusion duration may enhance the tissue uptake
of the drug, including tumour tissue.[29] Finally,
high Cmax of doxorubicin and doxorubicinol may
be associated with longer remission phases in pa-
tients with acute non-lymphocytic leukaemia.[32]
1.2 Epirubicin
Epirubicin is a semisynthetic derivative of
doxorubicin that has been extensively evaluated in
patients with breast cancer. It is effective in the
management of metastatic disease and as adjuvant
therapy in patients with early breast cancer.[34] In
the adjuvant setting, epirubicin-based therapy ap-
pears to have effectiveness at least equivalent to
that of cyclophosphamide, methotrexate and fluo-
rouracil (CMF); recent trials, predominantly in
premenopausal patients, report significant in-
crease in relapse-free and overall survivals for
epirubicin-based treatments as compared with
CMF.[35] In patients with metastatic disease,
epirubicin- and doxorubicin-containing regimens,
in combination with cyclophosphamide and fluo-
rouracil, are therapeutically equivalent.[35] The
major adverse effects of epirubicin are acute dose-
limiting myelotoxicity and cumulative dose-
related cardiotoxicity. Other important adverse ef-
fects include mucositis, nausea and vomiting,
reversible alopecia and local cutaneous reactions;
however, the tolerability of epirubicin is better
than that of doxorubicin at equimolar doses[35] and
the cardiotoxicity profile allows higher doses to be
administered with acceptable cardiac damage.[36]
Compared with doxorubicin, epirubicin pharma-
cokinetics are characterised by higher total body
clearance (CL) [mean 74.4 vs 18 to 30 L/h/m2],
shorter terminal half-life (mean 16.01 vs 20 to 70
hours) and larger Vss (mean 912 vs 700 L/m2), al-
beit highly variable among patients.[29,37] A small
fraction of epirubicin total dose (6 to 7%) is recov-
ered in the urine as such, less than 5% as glucuron-
© Adis International Limited. All rights reserved.
437
ides and epirubicinol, and 35% undergoes biliary
elimination mainly as metabolites, with a renal
clearance of epirubicin of only 7.39 ± 1.87 L/h/m2.
A clinical study of the administration of
epirubicin to patients with metastatic breast cancer
revealed no correlations of pharmacokinetic pa-
rameters with response to therapy or nausea/vomi-
ting. On the contrary, the AUC of epirubicin and
epirubicinol, the Cmax, the concentration at 2 hours
after administration and t1⁄2γ of epirubicin, corre-
lated with the occurrence of stomatitis.[21] PK-PD
correlations were observed between (see table I):
(i) epirubicin AUC and neutrophil nadir; [22] (ii)
first moment AUC (AUMC) and steady-state plasma
concentration (Cssp) and the area of the neutrophil-
time curve (AOC) below 4 000 cells/μl;[23] and (iii)
the logarithmic ratio of nadir/initial leucocyte
count and AUC of epirubicin alone as well as of
epirubicin plus epirubicinol.[24] However, a study
in patients with advanced malignancies treated
with epirubicin 90 to 150 mg/m2 failed to demon-
strate a relationship between Cmax or AUC of epiru-
bicin and the severity of haematological and non-
haematological toxicity. Furthermore, no difference
was noted between patients receiving bolus injec-
tion and 6-hour drug infusion, suggesting that Cmax
does not influence the occurrence of toxicity.[38]
1.3 Idarubicin
Idarubicin, a 4-demethoxy-anthracycline ana-
logue of daunorubicin, is an effective treatment for
acute myelogenous leukaemia and has also shown
activity in the treatment of advanced breast cancer,
multiple myeloma and non-Hodgkin’s lymphoma.
The absence of a methoxyl group at position 4 of
idarubicin results in increased lipophilicity and
cellular uptake compared with the related com-
pound daunorubicin. Idarubicin is more cytotoxic
than doxorubicin in vitro and its major metabolite,
idarubicinol, demonstrates similar activity to
idarubicin. The drug may be administered intrave-
nously or orally (bioavailability 30%); the dose-
limiting toxicity is leucopenia, while the incidence
of cardiotoxicity is lower than with doxoru-
bicin.[29]
Clin Pharmacokinet 2002; 41 (6)
438
A triphasic plasma decay of idarubicin was ob-
served after intravenous administration, with a
t1⁄2γ ranging from 6 to 35 hours, a large volume of
distribution (Vd) exceeding 1 800 L/m2 and a CL
of 30 to 122 L/h/m2.[39] After oral administration
of 2 to 10 mg/m2/day, significant correlations were
shown between absolute neutrophil count at nadir
and idarubicin AUC (r = –0.33, p = 0.022) and Cmax
(r = –0.38, p = 0.0067), and idarubicinol AUC (r =
–0.43, p = 0.0009) and Cmax (r = –0.41, p = 0.0016),
respectively (table I).[25]
1.4 Anthracycline Prodrugs
The clinical pharmacology of doxorubicin pro-
drugs may be summarised by taking into account
three representative compounds: N-L-leucyl-
doxorubicin, pirarubicin and valrubicin (AD-32).
Their pharmacokinetics have been evaluated with
respect to the release of the active drug doxo-
rubicin, which dictates the pharmacodynamic pro-
file of these agents.
N-L-Leucyl-doxorubicin has been administered
from 30 to 240 mg/m2; the drug is characterised by
linear pharmacokinetics, with a CL of 41.3 ± 25.7
L/h/m2.[11] N-L-Leucyl-doxorubicin is extensively
metabolised into doxorubicin, which appears in
plasma immediately after infusion of N-L-leucyl-
doxorubicin; the AUC values of N-L-leucyl-
doxorubicin, doxorubicin and doxorubicinol in-
crease linearly with drug dose. If compared with
the equimolar amount of the parent drug, the AUC
of doxorubicin generated by N-L-leucyl-doxo-
rubicin is approximately 23% of the AUC after ad-
ministration of doxorubicin. The prodrug charac-
teristics of N-L-leucyl-doxorubicin also affect the
rate of drug metabolism, since after administration
of N-L-leucyl-doxorubicin the AUC of doxo-
rubicinol is 73% of the AUC of doxorubicin, as
compared with 35% of the AUC of doxorubicin
after administration of doxorubicin itself. As ex-
pected, the toxicity profile of N-L-leucyl-doxo-
rubicin is similar to that of doxorubicin, with
myelosuppression (leucopenia and thrombocyto-
penia) and mucositis being the most serious ad-
verse events. A significant relationship could be
© Adis International Limited. All rights reserved.
Danesi et al.
established between the AUC of doxorubicin and
both white blood cell and neutrophil counts (table
I), whereas other adverse effects (thrombocyto-
penia or stomatitis) did not correlate with pharma-
cokinetic parameters.[27] These findings suggest that
the rate of metabolism of N-L-leucyl-doxorubicin
into doxorubicin is the main factor affecting the
occurrence and severity of adverse events.[11]
The PK-PD relationships of pirarubicin and
valrubicin are summarised in table I.
1.5 Anthracycline Delivery Systems
The administration of 20 to 320 mg/m2 of N-(2-
hydroxypropyl) methacrylamide (HPMA) copoly-
mer-bound doxorubicin (PK1) results in the slow
release of free doxorubicin, with concentrations
approximately 1000 times lower than unbound
doxorubicin.[15] The median distribution and elimin-
ation half-lives of the unbound doxorubicin were
estimated to be 2.7 and 49 hours, respectively, and
CL was as low as 0.194 L/h. The apparent CL of
free doxorubicin was 180 L/h, with distribution
and elimination half-lives of 0.13 and 85 hours,
respectively.[15]
Doxorubicin in polyethyleneglycol (PEG)-
coated liposomes displays a dose- and schedule-
dependent toxicity profile that is correlated with
pharmacokinetic parameters. Stomatitis is dose-
related, with higher incidence and severity at 60 to
70 mg/m2. Palmar-plantar erythrodysaesthesia
usually develops after more than two courses of
treatment and is schedule-dependent, with shorter
administration intervals leading to increased fre-
quency and severity. Leucopenia and neutropenia
are dose-dependent, but mild and uncomplicated in
most cases. Despite cumulative doses of up to
1500 mg/m2, cardiac toxicity is uncommon, al-
though more frequent in patients pretreated with
mitoxantrone and radiotherapy. The pharmacokine-
tics of doxorubicin released from PEG-liposomes
are described by a monoexponential elimination
curve with a long half-life (median 79 hours),
low CL (median 0.04 L/h) and a small Vd (median
3.9 L). Cmax and AUC increased linearly with the dose;
stomatitis and leucocyte nadir are correlated with
Clin Pharmacokinet 2002; 41 (6)
Pharmacokinetics-Pharmacodynamics of the Anthracyclines
dose and Cmax, less with AUC, whereas palmar-
plantar erythrodysaesthesia grade correlated sig-
nificantly with half-life (table I).[28]
1.6 New Anthracyclines
Third generation anthracyclines, with highly
potent in vitro cytotoxic activity, have been eva-
luated clinically, including the disaccharide
doxorubicin analogue MEN-10755 and methoxy-
morpholino-doxorubicin. MEN-10755, given in-
travenously weekly for 3 weeks at 15 to 45 mg/m2,
displayed a correlation between dose and AUC, a
mean AUC of 6 mg • h/L at 30 mg/m2, a CL of 5.6
L/h/m2 and a half-life of 15.3 hours. The maximal
tolerated dose (MTD) was 45 mg/m2 and dose es-
calation was prevented by neutropenia; however,
no PK-PD relationships were reported.[26]
Methoxymorpholino-doxorubicin, given orally
at doses from 59 to 940 μg/m2 once every 4 weeks
to patients with solid tumours, produced neu-
tropenia as the dose-limiting toxicity at the MTD
of 940 μg/m2. Unexpectedly severe neutropenia
and lack of relationship with plasma concentra-
tions of methoxymorpholino-doxorubicin and its
C-13 dihydro metabolite were observed, suggest-
ing the intracellular formation of potent cytotoxic
metabolites only present in human plasma in trace
amounts.[10] These findings underscore the com-
plexity of the pharmacology of newer anthracy-
clines with highly enhanced cytotoxic activity, and
the need for careful preclinical investigation be-
fore their use in the clinical setting.
2. Biological Basis of
Pharmacokinetic-Pharmacodynamic
Modelling
Anthracyclines are known for their complex
cytotoxic mechanism, involving intercalation be-
tween DNA base pairs by their positively charged
amino sugar moieties, which interact with the nega-
tively charged phosphate bridges of DNA. As a
consequence, anthracyclines interfere with DNA
strand separation and inhibit helicase, DNA
topoisomerase II and DNA and RNA polymerase
activities, which results in the inhibition of DNA
© Adis International Limited. All rights reserved.
439
replication and transcription, as well as induction
of DNA fragmentation. Anthracyclines exert addi-
tional cytotoxic effects mediated by inhibition of
cytochrome c oxidase activity, free radical forma-
tion and lipid peroxidation, producing direct mem-
brane effects, and chelation of iron and generation
of reactive oxygen species, resulting in oxidative
stress.[40,41] Recent studies provide evidence of a
caspase-dependent pathway in anthracycline-
induced apoptosis in leukaemic cells treated with
idarubicin and daunorubicin,[42] in normal lym-
phocytes[43] and in solid tumour cells following
treatment with doxorubicin.[44]
Experimental studies have provided evidence
that mitochondria are the main site of cardiac in-
jury and that oxidative stress is critically involved
in doxorubicin-induced heart injury, since transge-
nic mice overexpressing cardiac-specific metallo-
thionein are highly resistant to acute cardiotoxicity
induced by doxorubicin.[45] Clinically, a signifi-
cant protection against cardiac damage by anthra-
cyclines may be obtained with the iron-chelating
agent dexrazoxane.[46]
Two different parameters have been adopted to
assess the myelotoxic effect of a drug: the nadir,
the measure of the maximum level of neutrophil
fall with respect to the pretreatment value, and the
area over the curve (AOC), obtained by plotting
the neutrophil count as a function of time and cal-
culating the AOC below 4 000 cells/μl.[23] The ad-
ministration of anthracyclines affects the viability
of haematopoietic progenitor cells and impairs
their ability to maintain a normal output of differ-
entiated, nonproliferating cells, whereas the via-
bility and lifespan of leucocytes in peripheral
blood is unlikely to be reduced by treatment. These
observations have relevance to a better definition
of the concept of surviving fraction applied to pe-
ripheral blood cell counts as an estimate of the se-
verity of myelotoxicity.[47] The interval between
the administration of the anthracycline dose and
the reduction of neutrophils below baseline values
is approximately 10 days, and a further 4 to 6 days
are required to reach the nadir, for a total time lag
of 2 weeks.[23] Since the maturation of a committed
Clin Pharmacokinet 2002; 41 (6)
440
granulocyte stem cell to a mature neutrophil takes
about 10 days and, once in the systemic circulation,
granulocytes remain viable for about 8 to 12
hours,[48] it is clear that the definition of surviving
fraction applied to peripheral blood cells might sat-
isfy some PK-PD applications but does not reflect
the dynamics of the cytotoxic effect of anthracy-
clines on blood cells, and new investigations for
improved PK-PD modelling are required.
The development of a life-threatening form of
cardiomyopathy following treatment with anthra-
cyclines has also been the object of intensive in-
vestigation. Human myocardial tissue generates
doxorubicinol as well as doxorubicin deoxya-
glycone and doxorubicinol hydroxyaglycone, re-
flecting the ability of myocardial tissue to reduce
the side chain carbonyl group, as well as to perform
reductase- and hydrolase-type deglycosylation of
doxorubicin followed by carbonyl reduction, re-
spectively.[49] Commonly accepted hypotheses
have assigned a pivotal role to iron, which would
act as a catalyst for free radical reactions and oxi-
dative stress. However, the role of free radical–
based mechanisms in long-term effects has been
challenged. More recently, studies on the role of
C-13 hydroxy metabolites of anthracyclines have
provided new perspectives on the role of iron in the
cardiotoxicity of these drugs, and have shown that
the life-threatening chronic toxicity should be at-
tributed to alterations of iron homeostasis by
doxorubicinol.[49,50] Finally, intracellularly gener-
Drug-specific factors
Schedule of administration
PK
(bolus vs prolonged infusion)
Intrinsic activity
PD
(high potency - MMX-DXR vs lower potency - epirubicin)
Drug chemistry
PK
(prodrug vs active drug vs lipophilic drug)
Fig. 2. Diagrammatic representation of factors affecting the pharmacokinetic-pharmacodynamic (PK-PD) profile of anthracyclines.
AST = aspartate aminotransferase; MMX-DXR = methoxymorpholino-doxorubicin; PS = performance status.
© Adis International Limited. All rights reserved.
Danesi et al.
ated and highly cytotoxic metabolites of third-
generation anthracyclines, including methoxy-
morpholino analogues, will require further
consideration of the biological characteristics un-
derlying their pharmacodynamics in order to bet-
ter define the PK-PD relationships that will emerge
from clinical studies on activity and toxicity. An
integrated view of factors involved in PK-PD rela-
tionships of anthracyclines is reported in figure 2.
3. Theoretical Basis of
Pharmacokinetic-Pharmacodynamic
Modelling
Under pharmacokinetic steady-state conditions,
concentration-effect relationships can be described
by several pharmacodynamic models, which can
be classified as fixed effect, linear, log-linear,
maximum effect (Emax) and sigmoid Emax mod-
els.[51] Under non–steady-state conditions, how-
ever, more complex PK-PD models are required to
account for a temporal dissociation between drug
disposition and pharmacological effect.
The anthracyclines distribute into the bone mar-
row and elicit a response (decrease in cell count of
peripheral blood) that is delayed with respect to the
pharmacokinetic phase; the interval before the oc-
currence of toxicity is mainly dependent on the ef-
fect of anthracyclines on the kinetics of cellular
turnover within the bone marrow, while the gener-
ation of active metabolites and drug tissue distri-
Patient-specific factors
General conditions
PD (pretreatment PS and
organ function - bone marrow)
PK-PD
relationship
Metabolism/elimination
PK (age, nutritional status,
AST, bilirubin)
Clin Pharmacokinet 2002; 41 (6)
Pharmacokinetics-Pharmacodynamics of the Anthracyclines 441

bution are factors marginally related to the time lag Input

between administration and event. Assuming that kel kcc0
anthracyclines exert their effects on granulocyte
Peripheral k21 k13 Peripheral
precursors in the bone marrow, the most predictive shallow
Central deep
simulation of activity is the irreversible cell killing (Vps) 2 k12 (Vc) 1 k31 (Vpd) 3
pharmacodynamic model.[52-54] Important para- kicc
k1ec
meters in this model are: (i) production rate of ma- tlag kec1 −
Baseline
ture cells (i.e. neutrophils and platelets), a zero- Effect compartment Anthracyclines
E50
order process; and (ii) turnover rate of mature Progenitor +
cells, a first-order process. A graphic represent- (Vec) cells
Emax
t50/PK50 kck
ation of the PK-PD model is shown in figure 3. The
pharmacodynamic effect of cytotoxic agents has
been previously described using a counter-clock-
Fig. 3. Graphic representation of the pharmacokinetic-pharmaco-
wise hysteresis loop to correlate the observed phar- dynamic model of anthracyclines. Input = route of introduction
macological event with plasma concentrations un- of the drug in the body; central (Vc), peripheral shallow (Vps),
der conditions of a time delay between distribution peripheral deep (Vpd) and effect (Vec) compartments = body
compartments of drug distribution; kcc0 = rate constant of cell
and response. Moreover, the pharmacodynamic output from the central compartment (physiological turnover);
parameter survival fraction (SF), the ratio of the kel = rate constant of drug output from the central compartment;
number of cells of the affected tissue surviving af- k12/k21 and k13/k31 = intercompartmental rate constants; k1ec/kec1
= rate constants between the central and the effect compart-
ter exposure to a cytotoxic drug (e.g. doxorubicin) ments; kicc = rate constant of input of mature cells into the central
versus the number of cells before exposure, has compartment; kck = rate constant of progenitor cell kill by a cyto-
been used to describe the effect of doxorubicin on toxic agent (anthracycline); Progenitor cell = committed stem
cell to mature granulocyte or platelet; tlag = time interval between
mature circulating blood cells (neutrophils and drug administration and effect; Baseline, E50 and Emax = base-
platelets), and is defined as (equation 1): line cell count, 50% effect and maximal effect; t50/PK50 = time
interval to 50% reduction in cell count/pharmacokinetic param-
eter associated with 50% reduction in cell count. The positive
SF = e–kCt
and negative modulation of kck and kicc by anthracyclines is
shown in the graph.
where k is a constant determining the slope of the
dose-response curve, C is the drug concentration
and t is the time of exposure.[47] This relationship agent [anthracycline] (kck) and/or decrease in rate
directly relates the cellular effect of anthracycline constant of input of mature cells into the central
to the AUC, since the product C × t is equivalent compartment (kicc). The future challenge will be,
to AUC. This relationship, however, does not sat- therefore, the development of novel algorithms
isfy the underlying biology of cytotoxic agents and that incorporate parameters related to the cellular
does not explain the lack of relationship between biological factors sensitive to anthracyclines.
drug exposure and pharmacodynamics observed in
some studies. The counter-clockwise hysteresis 4. Clinical Application of
loop is suitable for describing effects that arise dur- Pharmacokinetic-Pharmacodynamic
ing drug exposure and reaches the maximum effect Relationship
while the agent is present in the plasma or tis-
sue;[47] however, bone marrow toxicity, as well as Anthracyclines are characterised by major
other toxicities involving cellular damage by inter- haematological and non-haematological toxicities
action with vital macromolecules (e.g. DNA) in- that call for careful administration of chemother-
duced by anthracyclines, appears when the drug is apy and represent the limiting factors that prevent
no longer detectable and it depends on increase in dose escalation or even the delivery of the standard
rate constant of progenitor cell kill by a cytotoxic drug dose. Moreover, the late development of toxi-

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (6)
442
city, as a result of unrecognised excessive drug ex-
posure due to one of the factors listed below, is a
cause of reduction of dose intensity with a lower
likelihood of clinical success. A number of factors
are responsible for the wide interpatient variation
of tolerability and activity of anthracyclines, and
they can be summarised as follows:
• intrinsic variability in drug disposition, includ-
ing Vss, CL and AUC
• abnormalities in excretory organ function, par-
ticularly liver
• intrinsic variability in bone marrow suscepti-
bility to anthracycline cytotoxicity.
In order to prevent the development of serious
adverse effects, therapeutic drug monitoring of an-
thracyclines should be performed, on the basis of
an established relationship between toxicity,
mainly haematological, and pharmacokinetic para-
meters, particularly systemic exposure (AUC), that
can be obtained, in the case of epirubicin, with the
following formula (equation 2):
AUC = 9.44 × C2 + 62.5 × C24 + 157.7
where C2 and C24 are the plasma concentrations
measured 2 and 24 hours after administration
(μg/L); this relationship is highly significant (r =
0.953, p < 0.05).[55] In order to reach a target AUC,
the dose may be further refined in the individual
patient with normal bilirubin concentrations by in-
troducing an estimate of liver integrity as assessed
by AST, as follows (equation 3):[29]
dose (mg/m2) = target AUC × (97.5 – 34.2 × log10 AST)
since AST levels (U/L) are related to the clearance
of anthracyclines, particularly doxorubicin. Fur-
thermore, strategies have been devised in order to
evaluate the predictability of changes in leucocyte
counts on the basis of plasma concentrations of
anthracyclines. One approach is applied to epiru-
bicin (equation 4):
log(leucocytenadir) = log(leucocyteinitial) – 0.0073 × C6 – 0.14
where C6 is a single measurement of drug concen-
tration (in μg/L) at 6 hours after treatment. Units
of leucocyte count are 109/L.[24] Again, this corre-
© Adis International Limited. All rights reserved.
Danesi et al.
lation was reported to be highly significant (r =
–0.59, p < 0.0001).
In the case of the doxorubicin prodrug
pirarubicin, its AUC in whole blood from time zero
to the end of infusion in patients given cumulative
doses up to 90 mg may be calculated as follows
(equation 5):
AUC = (Cinf × tinf)/2
where Cinf is the concentration of pirarubicin in
whole blood at the end of infusion and tinf is the
length of infusion. Once the AUC is defined, a for-
mula to predict leucocyte count at the nadir (ap-
proximately 12 days after treatment), on the basis
of a single sample of blood obtained at the end of
drug administration, may be established (equation
6):
leucocytenadir = 0.032404 × age + 2.005 +
leucocyteinitial × e(–0.009316 × AUC + 4.202265)
with leucocyte count expressed as 10 3 cells/μl and
the AUC of pirarubicin from time zero to the end
of infusion as μg • h/L. Bias and precision of this
model are 0.001 and 25.8%, respectively, and r =
0.809. The prediction of the extent of leucopenia
allows the anticipation of serious haematological
toxicity and the decision whether or not to start
prophylactic treatment with haematopoietic
growth factors.[12]
5. Conclusions
A clear PK-PD correlation has been demon-
strated for some anticancer drugs, including an-
thracyclines, and this relationship provides a back-
ground against which rational dose optimisation
can be implemented for individual patients.[1] Un-
fortunately, PK-PD modelling has played a rather
limited role in the clinical use of anthracycline anti-
cancer drugs. Methodological issues, limited inter-
actions between the clinical pharmacologist and
the oncologist and the need to move novel active
schedules rapidly to phase III of clinical develop-
ment have restricted the opportunity for clinical
pharmacology analysis in phase I/II clinical trials.
Another cause of suboptimal application of phar-
Clin Pharmacokinet 2002; 41 (6)
Pharmacokinetics-Pharmacodynamics of the Anthracyclines
macokinetic studies is that therapeutic drug moni-
toring would not be easy to perform, due to the
large number of blood samples required, unless
adaptive dosage adjustments with feedback con-
trol are applied with a limited sampling strategy,
thus allowing a feedback adjustment of dosage fol-
lowing measurement of plasma drug concentration
and comparison with population pharmacokinetic
values.[1] The application of PK-PD procedures to
the clinical setting is warranted in order to reduce
toxicity and to give the full chemotherapy dose
under safe conditions. Finally, the PK-PD ap-
proach is a theoretical strategy that has not, until
now, been used prospectively in clinical oncology.
However, the availability of simple PK-PD algo-
rithms to be applied in the clinical setting is poten-
tially of enormous, although still underestimated,
clinical value. Collaboration with a clinical phar-
macology service for drug monitoring will help
clinicians to deliver drugs in safer conditions in
order to achieve controlled neutropenia and maxi-
mise the dose to be administered.
Acknowledgements
This work was supported in part by research grants from
the University of Pisa to Romano Danesi. There are no
potential conflicts of interest relevant to the contents of this
article.
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Correspondence and offprints: Dr Romano Danesi, Division
of Pharmacology and Chemotherapy, Department of On-
cology, Transplants and Advanced Technologies in Medi-
cine, University of Pisa, Via Roma 55, Pisa, I-56126, Italy.
E-mail: r.danesi@med.unipi.it
Clin Pharmacokinet 2002; 41 (6)