Drugs 45 (Suppl. 2): 20-30, 1993
`0012-6667/93/0200-0020/$5.50/0
`© Adis International Limited. All rights reserved.
`
`DRSUP3592
`
`Epirubicin
`Clinical Pharmacology and Dose-Effect Relationship
`
`Jacques Robert
`Fondation Bergonie, Bordeaux, France
`
`Summary
`
`The pharmacokinetic properties of epirubicin are characterised by a triphasic plasma clear(cid:173)
`ance, with half-lives for the initial (a), intermediate (fJ) and terminal ('Y) elimination phases of
`approximately 3 minutes, I hour and 30 hours, respectively. These values are similar to or slightly
`shorter than the corresponding half-lives of doxorubicin. The total plasma clearance of epirubicin
`is approximately 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. This dif(cid:173)
`ference is mainly due to the relatively high volume of distribution of epirubicin, and the unique
`glucuronidation metabolic pathway of epirubicin and epirubicinol, which is not available to do x(cid:173)
`orubicin or doxorubicinol. Glucuronide metabolites of epirubicin and epirubicinol are not active
`per se, but could divert epirubicin from free radical formation, which may induce cardiotoxic
`effects. This may explain, at least in part, the lower cardiotoxicity of this new anthracycline
`relative to that of the parent compound. There is a linear relationship between the dose admin(cid:173)
`istered and area under the plasma concentration-time curve (AUC) values of both unchanged
`drug and metabolites, so that the total plasma clearance of epirubicin is constant with epirubicin
`doses ranging from 40 to 140 mg/m2. No variation in total plasma clearance as a function of
`age in the range of 31 to 74 year.s has been observed, and this parameter is unaffected by sub(cid:173)
`sequent courses of treatment. Hepatic dysfunction causes an increase in the terminal elimination
`half-life of epirubicin, which is well correlated with serum bilirubin levels and which necessitates
`a reduction in epirubicin dosage.
`Epirubicin is responsible for a dose-dependent neutropenia, which is clearly related to drug
`exposure as established in pharmacodynamic studies. The maximum tolerated dose (MTD) of
`epirubicin was first established to be approximately 90 mg/m2 but this was re-examined recently
`and is now deemed to be approximately 150 mg/m2, which is about 2-fold higher than the MTD
`of doxorubicin. Cumulative cardiac toxicity occurs for both epirubicin and doxorubicin, but the
`dose ratio for equal risk is about 1.8 in favour of epirubicin (500 to 550 mg/m2 for doxorubicin
`vs 900 to 1000 mg/m2 for epirubicin). Consequently, there is not a higher risk of developing
`cardiotoxicity after administration of high dose epirubicin, since this adverse effect is associated
`with total cumulative anthracycline dose. In several controlled trials, epirubicin exhibited the
`same anticancer activity as doxorubicin when administered at equimolar doses to patients with
`advanced breast cancer. When used in high dose regimens, either as a single agent or in com(cid:173)
`bination with other cytotoxic drugs, response rates were significantly increased in most studies,
`with acceptable immediate toxicity and no increase in cardiac risk. Together, these factors justify
`the use of epirubicin as adjuvant therapy in patients with breast cancer of poor prognosis.
`
`AVENTIS EXHIBIT 2021
`Mylan v. Aventis
`IPR2016-00627
`
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`

`
`Clinical Pharmacology of Epirubicin
`
`21
`
`o
`
`OH
`
`Fig. 1. Structural formula of epirubicin. The ketone moiety
`of C-13 is reduced in epirubicinol; the hydroxyl group of C-
`4' is axial in doxorubicin and equatorial in epirubicin, which
`allows conjugation of epirubicin with glucuronic acid.
`
`Epirubicin (4'-epidoxorubicin) is a new anthra(cid:173)
`cycline that is commercially available in several
`countries; it was selected on the basis of its activity
`against a broad range of tumours (Arcamone et al.
`1975; Casazza 1979) and reduced cardiac toxicity
`(Bertazzoli et al. 1985; Casazza 1979) in experi(cid:173)
`mental models. Epirubicin differs from doxorubi(cid:173)
`cin only in the spatial orientation of the 4' hy(cid:173)
`droxyl moiety (fig. 1). Epirubicin behaves like
`doxorubicin in several in vitro systems (Hill &
`Whelan 1982; Plumbridge & Brown 1978), but has
`a higher cellular uptake than doxorubicin, proba(cid:173)
`bly because of its lower pKa and higher lipophil(cid:173)
`icity. In addition, from a metabolic and phar(cid:173)
`macokinetic perspective, epirubicin exhibits some
`unique features. This paper reviews its clinical
`pharmacology, with special emphasis on the high
`dose protocols that have recently been developed
`for the treatment of advanced breast cancer.
`
`1. Clinical Pharmacology
`1.1 Pharmacokinetic Properties
`
`A number of studies have evaluated the phar(cid:173)
`macokinetic properties of epirubicin after intra(cid:173)
`venous administration of doses ranging between 20
`and 150 mg/m2. An overview of the main phar(cid:173)
`macokinetic parameters measured in these studies
`
`is presented in table I. Figure 2 demonstrates rep(cid:173)
`resentative triphasic plasma decay of epirubicin and
`doxorubicin in patients with breast cancer after
`administration of an intravenous bolus of 50 mg/
`m2. Successive half-lives of epirubicin were ap(cid:173)
`proximately 3 minutes, 1 hour and 30 hours, which
`were slightly shorter than those observed for doxo(cid:173)
`rubicin in crossover studies (Camaggi et al. 1988;
`Eksborg et al. 1986a; Mross et al. 1988). Further(cid:173)
`more, as illustrated in figure 2, plasma levels
`achieved after epirubicin administration were con(cid:173)
`sistently lower than those obtained after doxorub(cid:173)
`icin administration. As a result, the total plasma
`clearance of epirubicin was approximately 50 to
`100% higher than that of doxorubicin (50 vs 30
`L/h/m2), which reflects both a major supplemen(cid:173)
`tary metabolic pathway for epirubicin and sub(cid:173)
`stantial tissue penetration, as shown by the high
`volume of distribution of epirubicin compared with
`that of doxorubicin (1000 vs 500 L/m2).
`When epirubicin was administered as a pro(cid:173)
`longed infusion, the pharmacokinetic parameters
`remained unchanged (de Vries et al. 1987; Robert
`& Bui 1992; Workman 1992). The main charac(cid:173)
`teristic of this type of administration is the rela(cid:173)
`tively short time required to achieve steady-state
`plasma concentrations « 24 hours), despite the
`protracted half-life of the drug. There is a good lin(cid:173)
`ear relationship between the dose administered and
`the values for area under the plasma concentra(cid:173)
`tion-time curve (AUC) of both unchanged drug and
`metabolites, so that the total plasma clearance of
`epirubicin is constant over the dosage range of 40
`to 140 mg/m2 (Jakobsen et al. 1991a). No signifi(cid:173)
`cant variation in total plasma clearance as a func(cid:173)
`tion of age in the range of 31 to 74 years has been
`observed, and this parameter remains unchanged
`after subsequent courses of treatment (Jakobsen et
`al. 1991a). Hepatic dysfunction causes an increase
`in the terminal elimination half-life of epirubicin,
`which is well correlated with serum bilirubin levels
`and which necessitates epirubicin dosage reduction
`(Camaggi et al. 1982; Jakobsen et al. 1991a). Sev(cid:173)
`eral investigators have studied intrahepatic admin(cid:173)
`istration of epirubicin through the hepatic artery
`(Eksborg et al. 1986b; Pannuti et al. 1986; Strocchi
`
`

`
`22
`
`Drugs 45 (Supp/. 2) 1993
`
`Table I. Pharmacokinetic parameters of epirubicin
`
`Reference
`
`No. of
`courses
`
`Dose
`(mg/m2)
`
`t'ha
`(min)
`
`t'hp
`(h)
`
`tv.,
`(h)
`
`CL
`(L/h/m2)
`
`Vdss
`(L/m2)
`
`tv. metab
`(h)
`
`AUCmetab:
`AUCdrug
`
`11
`
`14
`
`8
`
`6
`
`27
`
`107
`
`60-90
`
`30-90
`
`60
`
`20
`
`75
`
`40.0
`
`30.5
`
`1844
`
`39.4
`
`48.0
`
`1856
`
`32.2
`
`2.92
`
`1.08
`
`31.4
`
`43.1
`
`1272
`
`3.40
`
`0.89
`
`13.9
`
`71.5
`
`5.4
`
`1.7
`
`44.8
`
`29.0
`
`2964
`
`0.25
`
`0.37
`
`0.35
`
`0.18
`
`40-135
`
`20.6
`
`50.9
`
`838
`
`18.1
`
`Camaggi et al.
`(1982)
`Camaggi et al.
`(1985)
`Camaggi et al.
`(1988)
`Eksborg et al.
`(1986a)
`Hu et al.
`(1989)
`Jakobsen et al.
`(1991a)
`Martini et al.
`(1984)
`Mross et al.
`(1988)
`Robert et al.
`(1985)
`Tjuljandin et al.
`(1990)
`Vrignaud et al.
`(1985)
`Weenen et al.
`(1983)
`
`8
`
`8
`
`9
`
`52
`
`10
`
`8
`
`70
`
`3.15
`
`1.25
`
`30.1
`
`84.2
`
`2332
`
`40-60
`
`1.80
`
`0.49
`
`15.3
`
`50.1
`
`50
`
`3.44
`
`1.12
`
`18.3
`
`37.0
`
`592
`
`583
`
`31.5
`
`21.1
`
`90-150
`
`10
`
`42.0
`
`46-111
`
`25-35
`
`2.53
`
`1.04
`
`29.3
`
`41.5
`
`925
`
`21.1
`
`75-90
`
`4.8
`
`2.6
`
`38.0
`
`94.9
`
`1432
`
`0.20
`
`0.62
`
`0.26
`
`0.64
`
`Abbreviations: tv.. = half-life of initial phase; tV'd = half-life of intermediate phase; tv.> = half-life of terminal elimination phase;
`tv. metab = elimination half-life of epirubicinol; CL = total plasma clearance; Vdss = volume of distribution at steady-state; AUCmetab : AUC
`drug = area under the concentration-time curve ratio of epirubicinol to epirubicin.
`
`et al. 1985). The elimination curves obtained un(cid:173)
`der these conditions are similar to those obtained
`after intravenous administration, but systemic
`plasma drug concentrations were lower and total
`plasma clearance was 1.5- to 2-fold higher with in(cid:173)
`trahepatic administration. Other routes of epirub(cid:173)
`icin administration have been tested, such as in(cid:173)
`traperitoneal (Strocchi et al. 1985) and intravesical
`instillations (Mross et al. 1987), but have not yet
`become routine clinical practice.
`
`1.2 Metabolism and Elimination
`
`Epirubicin undergoes extensive metabolism, in(cid:173)
`cluding conversion to a 13-dihydro metabolite,
`epirubicinol. The enzyme responsible for this
`metabolic pathway is aldoketoreductase, which is
`
`able to reduce most anthracyclines, with different
`rates and affinities for the specific agents (Loveless
`et al. 1978). As with doxorubicinol, epirubicinol
`remains quantitatively less important than the par(cid:173)
`ent drug, and displays only minimal cytotoxic ac(cid:173)
`tivity (Schott & Robert 1989). 7-Deoxyaglycone
`metabolites of epirubicin are also generally found
`in plasma after epirubicin administration; how(cid:173)
`ever, concentrations are low and are not detectable
`in all patients.
`It was first recognised by Weenen et al. (1983,
`1984) that, in humans, epirubicin could undergo
`conjugation with glucuronic acid as a result of the
`equatorial orientation of the hydroxyl moiety in
`the C-4' position. High concentrations of glucu(cid:173)
`ronides of both epirubicin and epirubicinol are
`found in plasma (Robert et al. 1985; Vrignaud et
`
`

`
`Clinical Pharmacology of Epirubicin
`
`23
`
`al. 1985) [fig. 3]. These glucuronide compounds
`display no cytotoxicity, but it has been suggested
`that they could divert epirubicin from the redox
`cycle, which leads to the formation of free radicals
`(activated oxygen species). These free radicals are
`thought to account, at least in part, for cardiac tox(cid:173)
`icity. Therefore, this metabolic pathway may result
`in the better cardiac tolerability of epirubicin.
`However, this is merely a hypothesis, and the pos(cid:173)
`sible roles of epirubicin conjugation have not been
`studied in detail. We have documented a bimodal
`distribution of patients with respect to metabolic
`transformation of epirubicin, and improved tol(cid:173)
`erability in patients having a low metabolite vs un(cid:173)
`changed drug ratio (Robert et al. 1990).
`As with other anthracyclines, urine remains a
`minor route of excretion, not exceeding 20% of an
`administered dose. Biliary excretion has been stud(cid:173)
`ied extensively by Camaggi et al. (1986), who found
`a cumulative excretion of approximately 40% over
`3 days. Considered altogether, half of a doxorubi(cid:173)
`cin dose is eliminated and accounted for in 7 days
`following administration, whereas half of an epi-
`
`rubicin dose is eliminated and accounted for in 4
`days.
`
`1.3 Pharmacokinetic-Pharmacodynamic
`Relationships
`
`In a very detailed study performed in 55
`patients, Jakobsen et al. (199Ib) were able to show
`a positive correlation between the AUC and mye(cid:173)
`lotoxicity of epirubicin in the dosage range of 40
`to 135 mg/m2. The logarithm of the surviving frac(cid:173)
`tion of white blood cells (WBC) was strongly de(cid:173)
`pendent upon the AUC of epirubicin, either un(cid:173)
`changed or together with epirubicinol (r = -0.55).
`This correlation was clearly maintained when only
`1 or 2 time-points were selected with a limited
`sampling model, and allowed good predictability
`of WBC nadirs after drug administration. It has
`been suggested that such plasma concentration
`evaluations could be used to determine whether the
`nadir expected falls below an acceptable limit, thus
`indicating the need for haemopoietic support with
`colony-stimulating factors (CSFs).
`
`10000
`
`• Doxorubicin (n = 7)
`• Epirubicin (n = 9)
`
`1000
`
`~
`2:
`
`c: t 100
`
`B c:
`8
`01
`E
`Ul
`01
`0::
`
`10
`
`1+-----~--~~--~-----r----------~--------~----------_,
`o
`20
`40
`30
`50
`10
`
`Time (hours)
`
`Fig. 2. Comparative plasma decay curves of doxorubicin and epirubicin after intravenous bolus administration of
`50 mg/m2 in patients with breast cancer (mean ± SO).
`
`

`
`24
`
`Drugs 45 (Suppi. 2) 1993
`
`• Epirubicin
`A Epirubicin glucuronide
`[J Epirubicinol A Epirubicinol glucuronide
`
`10000
`
`1000
`
`100
`
`10
`
`10000
`
`1000
`
`100
`
`10
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`;;"!
`0>
`2:
`c
`
`! c
`
`2l
`c
`8
`as
`E
`~ c...
`
`1+---------~----~--_r----~--_,----------r_--~----~
`o
`10
`20
`30
`50
`40
`
`Time (hours)
`
`Fig. 3. Plasma concentration vs time curves of epirubicin and its metabolites derived from mean values in 9 patients following
`intravenous administration of 50 mg/m2.
`
`It is much more difficult to determine a rela(cid:173)
`tionship between pharmacokinetic parameters and
`drug efficacy. Hu et aI. (1989) have observed that
`response to the drug occurred more frequently when
`the AVC of epirubicin was high.
`
`2. Dose-Effect Relationships:
`Comparison with Doxorubicin
`
`During the early development of epirubicin, the
`maximum recommended dose was between 75 and
`90 mg/m2, with leucopenia as the dose-limiting
`toxicity (Ganzina 1983). On this basis, a number
`of phase II and III studies have utilised doses in
`the range of 60 to 80 mg/m2 administered every 3
`weeks (see review by Mouridsen et al. 1990). Re(cid:173)
`cently, the maximum tolerated dose has been reas(cid:173)
`sessed, and is now estimated to be approximately
`150 to 180 mg/m2 in low risk patients and 105 to
`120 mg/m2 in previously treated patients (Case et
`al. 1987, 1988). In the following sections we have
`reviewed the efficacy and toxicity of epirubicin at
`standard (or conventional) doses (60 to 90 mg/m2)
`
`compared with the efficacy and toxicity of doxo(cid:173)
`rubicin, and the impact of using high dose (100 to
`180 mg/m2) regimens of epirubicin.
`
`2.1 Efficacy and Toxicity of Epirubicin vs
`Doxorubicin with Single-Agent and
`Combination Regimens
`
`Bone marrow toxicity is the dose-limiting acute
`toxicity associated with epirubicin and doxorubi(cid:173)
`cin administration. Mouridsen (1990) evaluated
`several single-agent comparative randomised stud(cid:173)
`ies, and demonstrated slightly lower myelotoxicity
`with epirubicin. The dosage ratio of doxorubicin :
`epirubicin that achieved equivalent haematological
`toxicity was approximately 1 : 1.2. In another lit(cid:173)
`erature analysis, Herait et al. (1992) observed grade
`3 to 4 leucopenia in 40% of patients treated with
`75 mg/m2 doxorubicin and in 20% of patients
`treated with 85 to 90 mg/m2 epirubicin. These re(cid:173)
`sults also demonstrated that epirubicin is less mye(cid:173)
`lotoxic than doxorubicin. Potentially lethal cardio(cid:173)
`toxic effects remain an important concern with
`
`

`
`Clinical Pharmacology of Epirubicin
`
`25
`
`anthracycline treatment. When the risk of con(cid:173)
`gestive heart failure (CHF) as a function of dose
`was plotted, an equitoxic cumulative dose ratio for
`doxorubicin: epirubicin of approximately 1.7-2 was
`obtained in both reviews. The cumulative dose
`giving an unacceptable risk of CHF was approxi(cid:173)
`mately 500 to 550 mg/m2 for doxorubicin and 900
`to 1000 mg/m2 for epirubicin. Thus, it is possible
`to administer a maximum of 9 courses of doxo(cid:173)
`rubicin 60 mg/m2 compared with 13 courses of
`epirubicin 75 mg/m2.
`Numerous phase II and III clinical trials have
`been conducted using epirubicin, as a single agent
`or in combination with other cytotoxic drugs, par(cid:173)
`ticularly in the treatment of advanced breast can(cid:173)
`cer. Doxorubicin and epirubicin, administered at
`equimolar or equimyelotoxic doses, have achieved
`similar response rates in patients with advanced
`breast cancer (table II), and lower toxicity was often
`observed with epirubicin (table III). On the basis
`of a meta-analysis of 16 trials including a total of
`479 patients receiving doxorubicin and 219 receiv-
`
`ing epirubicin, Herait et al. (1992) did not observe
`any difference between treatment groups in terms
`of response rates.
`The therapeutic equivalence of epirubicin and
`doxorubicin at equimolar doses is therefore well
`documented. In view of the reduced toxicity of epi(cid:173)
`rubicin, it was therefore decided by some investi(cid:173)
`gators to take advantage of the dose-response effect
`of anthracyclines (Jones et al. 1987; O'Bryan et al.
`1977; Wheeler et al. 1982) by increasing the dose
`administered with the aim of increasing response
`rates.
`
`2.2 Efficacy and Toxicity
`of High Dose Epirubicin Regimens
`in Advanced Breast Cancer
`
`Clinically effective doses of epirubicin are gen(cid:173)
`erally in the range of 75 to 90 mg/m2, and those
`of doxorubicin are in the range of 60 to 75 mg/m2;
`the corresponding dose ratio of doxorubicin : epi(cid:173)
`rubicin deemed to achieve equal efficacy ranges
`
`Table II. Efficacy of doxorubicin and epirubicin in comparative studies of advanced breast cancer
`
`Reference
`
`Doxorubicin
`
`no. of
`patients
`
`dose
`(mgjm2)a
`
`response
`rate
`(%)
`
`response
`duration
`(months)
`
`Epirubicin
`
`no. of
`patients
`
`dose
`(mgjm2)a
`
`response
`rate
`(%)
`
`response
`duration
`(months)
`
`21
`
`21
`
`21
`
`28
`
`75
`
`20b
`
`60
`
`60
`
`52
`
`38
`
`29
`
`25
`
`Single agent
`Brambilla et al.
`(1986)
`Gasparini et al.
`(1991 )
`Hortobagyi et al.
`(1989)
`Jain et al.
`(1985)
`Combination with fluorouracil and cyclophosphamide
`50
`52
`French Epirubucin 113
`Study Group
`(1988)
`Italian Multicenter 221
`Breast Study
`(1988)
`
`50
`
`57
`
`a Administered every 3 weeks unless otherwise specified.
`b Administered every week.
`
`13
`
`7
`
`5
`
`7
`
`12
`
`10
`
`21
`
`22
`
`27
`
`24
`
`117
`
`222
`
`75
`
`20b
`
`90
`
`85
`
`50
`
`50
`
`62
`
`36
`
`26
`
`25
`
`50
`
`54
`
`11
`
`4.5
`
`4
`
`12
`
`9
`
`9
`
`

`
`26
`
`Drugs 45 (Suppl. 2) 1993
`
`Table III. Toxicity of doxorubicin and epirubicin in comparative studies of advanced breast cancer
`
`Doxorubicin
`
`no. of
`patients
`
`dose
`(mg/m2)a
`
`Epirubicin
`
`leucopenia
`grade 3-4
`(% of
`cycles)
`
`congestive
`heart failure
`(% of patients)
`
`no. of
`patients
`
`dose
`(mg/m2)a
`
`leucopenia
`grade 3-4
`(% of
`cycles)
`
`congestive
`heart failure
`(%"of
`patients)
`
`21
`
`21
`
`21
`
`28
`
`75
`
`20c
`
`60
`
`60
`
`Single agent
`Brambilla et al.
`(1986)
`Gasparini et al.
`(1991)
`Hortobagyi et al.
`(1989)
`Jain et al.
`(1985)
`Combination with fluorouracil and cyclophosphamide
`French Epirubicin
`113
`50
`5
`Study Group
`(1988)
`Italian Multicenter 221
`Breast Study
`(1988)
`
`18
`
`5
`
`18
`
`25
`
`0
`
`0
`
`10
`
`25b
`
`21
`
`22
`
`27
`
`24
`
`75
`
`20c
`
`90
`
`85
`
`3
`
`117
`
`50
`
`7
`
`0
`
`35
`
`25
`
`3
`
`1.6
`
`222
`
`50
`
`15
`
`0
`
`0
`
`5
`
`20b
`
`0
`
`0.4
`
`50
`
`28
`
`a Administered every 3 weeks unless otherwise specified.
`b Congestive heart failure occurred in this study at a cumulative dose of epirubicin twice as high as that of doxorubicin.
`c Administered every week.
`
`from 1 : 1 to 1 : 1.5 (Praga et al. 1991). Numerous
`phase II studies have been undertaken to evaluate
`the feasibility of high dose epirubicin therapy in
`advanced breast cancer and other malignancies.
`Overall, a substantial body of experimental evi(cid:173)
`dence is available to support the correlation of
`cytotoxicity for both tumour and host cells with
`the amount of drug given per unit-time, i.e. the
`drug-dose intensity (Hryniuk & Bush 1984; Hry(cid:173)
`niuk et al. 1987). Yet the shape and slope of such
`a dose-response curve are influenced by a host of
`factors, such as chemosensitivity of the given tum(cid:173)
`our type, tumour size, tumour kinetics and multi(cid:173)
`drug resistance.
`The availability of blood products, together with
`adequate antibiotic support and the possibility of
`stimulating bone marrow recovery with either hae(cid:173)
`mopoietic growth factors or peripheral blood stem
`cells, enables the clinician to diminish the intensity
`of haematological toxicity and use highly myelo-
`
`suppressive doses of epirubicin with an acceptable
`risk to the patient (Hortobagyi 1990; Neidhart 1992;
`Rowe and Rapoport 1992). Reduced myelotoxicity
`of epirubicin relative to that of doxorubicin is a
`prerequisite for the use of such a dose intensifi(cid:173)
`cation in an effort to enhance therapeutic efficacy
`in anthracycline-sensitive tumours, such as breast
`carcinoma.
`Phase II studies evaluating the feasibility of high
`dose epirubicin treatment in advanced breast can(cid:173)
`cer and other malignancies (table IV) obtained
`overall response rates of 85, 78, 69, 65 and 35%
`with doses of 180, 150, 120, 120 and 110 mg/m2,
`respectively, clearly showing that the probability of
`response was strongly dependent upon the dose ad(cid:173)
`ministered (Bezwoda et al. 1991; Carmo-Pereira et
`al. 1991; Fountzilas et al. 1991; Neri et al. 1989;
`Sledge et al. 1992). It was necessary for those data
`to be confirmed by controlled trials. Several ran(cid:173)
`domised trials were performed comparing epirub-
`
`

`
`Clinical Pharmacology of Epirubicin
`
`27
`
`icin at 2 dosage levels, usually in combination with
`other cytotoxic agents (table IV). In a study by the
`French Epirubicin Study Group (1991), no differ(cid:173)
`ences in response rate or toxicity were observed
`between epirubicin doses of 50 and 75 mg/m2 when
`combined with 5-fluorouracil plus cyclophosph(cid:173)
`amide, although the proportion of complete re(cid:173)
`sponses was significantly greater with the higher
`dosage regimen. By increasing the epirubicin dose
`up to 100 mg/m2 in a study combining only pred(cid:173)
`nisolone with the anthracycline, Habeshaw et al.
`(1991) noted an increase in the response rate from
`23 to 41 %. However, tolerability was significantly
`reduced and no improvement was detected in sur-
`
`vival. Focan et al. (1991) also compared regimens
`of epirubicin 50 and 100 mg/m2 in combination
`with 5-fluorouracil plus cyclophosphamide, the 100
`mg/m2 dose being fractionated on days 1 and 8.
`They also obtained a significant increase in re(cid:173)
`sponse rate (41 vs 69%, respectively) with increased
`toxicity, but time to progression was also longer
`among patients receiving the higher dosage. In a
`nonrandomised trial, increasing the dose from 60
`to 120 mg/m2 increased the response rate from 35
`to 67% (Neri et al. 1991). Figure 4 summarises the
`dose-response relationship of epirubicin in ad(cid:173)
`vanced breast cancer as obtained from the various
`phase II and III studies cited below. Similar dose-
`
`Table IV. Dose-response relationship in phase II and III studies of epirubicin (EPI) in advanced breast cancer
`
`Reference
`
`No. of patients
`
`Dose
`(mg/m2)8
`
`Response rate
`("!o)
`
`Duration of response
`(months)
`
`Phase II studies
`EPI as a single agent
`Bezwoda et al. (1991)
`Carmo-Pereira et al. (1991)
`Fountzilas et al. (1991)
`Neri et al. (1989)
`Sledge et al. (1992)
`Walde & Bettello (1991)
`
`EPI + cyclophosphamide
`Marschner et al. (1990)
`Martin et al. (1991)
`Pieeart et al. (1991)
`
`Phase III studies
`Combination with cyclophosphamide
`and fluorouracil
`Foean et al. (1991)
`
`French Epirubiein Study
`Group (1991)
`
`EPI as a single agent
`Habeshaw et al. (1991)
`
`Neri et al. (1991)C
`
`50
`40
`48
`22
`20
`31
`
`34
`17
`16
`
`71
`70
`
`121
`123
`
`100
`102
`
`23
`27
`
`a Administered every 3 to 4 weeks.
`b Administered in divided doses on days 1 and 8.
`e Nonrandomised study.
`
`150
`120
`110
`120
`180
`100-180
`
`120
`120
`120
`
`50
`100b
`
`50
`75
`
`50
`100
`
`60
`120
`
`78
`65
`35
`69
`85
`65
`
`73
`94
`94
`
`41
`69
`
`45
`45
`
`23
`41
`
`35
`67
`
`11+
`7
`6
`15
`7
`8+
`
`14
`
`14
`22
`
`13
`15
`
`5
`7
`
`7
`10
`
`

`
`28
`
`Drugs 45 (Suppl. 2) 1993
`
`100
`
`(4,5,6)
`
`3. Conclusion
`
`CD
`
`~ 80
`N 60
`CD
`<II c:
`0
`Co
`<II
`CD
`a:
`
`40
`
`20
`
`Combination
`
`(1,3)
`
`(2)
`
`Single-agent
`
`According to the evidence presented, epirubicin
`may be considered as an agent distinct from the
`parent compound, doxorubicin, with unique but
`overlapping activity and toxicity profiles. Both high
`dose and standard dose epirubicin regimens have
`been effective in the treatment of breast cancer. The
`potential superiority of high dose epirubicin should
`therefore be analysed in adjuvant or neoadjuvant
`therapy of high risk patients. An increased inci(cid:173)
`dence of clinical cardiotoxicity has not been ob(cid:173)
`served when high dose epirubicin regimens with
`cumulative doses of 900 to 1000 mg/m2 are used.
`The increased acute toxicity remains within the
`limits of acceptability, and pharmacokinetic moni(cid:173)
`toring of epirubicin appears to be quite feasible and
`would allow the prediction of granulocyte nadirs.
`The combined use ofhaemopoietins, such as CSFs,
`interleukin-3 and interleukin-6, could, on an in(cid:173)
`dividual basis, therefore help rescue patients at risk
`of leucopenia.
`
`Acknowledgement
`
`Personal contributions of the author were performed
`with the participation of the clinicians of Fondation Ber(cid:173)
`gonic, the Comprehensive Cancer Center of Bordeaux,
`especially Drs N.B. Bui, J. Chauvergne, M. Durand, H.
`Eghbali, B. Hoemi and L. Mauriac, with the technical
`assistance of Mrs C. Garcia, S. Huet and C. Nassi. Mrs
`D. Quincy is gratefully acknowledged for typing the man(cid:173)
`uscript.
`
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`exists, is still valid and safe for patients receiving
`higher doses.
`
`

`
`Clinical Pharmacology of Epirubicin
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