ABSTRACT
`
`Objective: The aim of this study was to describe the pharmacokinetics of 3
`different single doses of fulvestrant—a new estrogen receptor (ER) antagonist that
`downregulates the ER with no known agonist effects—administered as a prolonged-
`telease IM formulation.
`Methods: Pharmacokinetic data were obtained in a randomized, partially
`blinded, placebo-controlled, parallel-group, Phase I/II multicentertrial involving
`postmenopausal women with primary breast cancer (clinical stages T1-T3, with
`tumors that were ER positive or of unknown ERstatus) awaiting curative-intent
`surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral ta-
`moxifen (20 mg, once daily), or oral placebo (once daily). Treatmentstarted 2 to
`3 weeks before surgery and blood wastaken at various times up to 12 weeksaf-
`ter fulvestrant administration to assess pharmacokinetic variables.
`Results: A total of 200 patients entered thetrial, of whom 58 took part in the
`pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22).
`Following single IM injections of fulvestrant, the median time to maximum con-
`centration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mgdose groups,
`respectively, with an overall range of 2 to 19 days). The plasma concentration—
`time profiles were primarily controlled by the rate of absorption from the injec-
`tion site; post-peak plasma concentrations declined over time and were measur-
`able up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma
`
`Accepted for publication February 28, 2003.
`Printed in the USA. Reproduction in whole or part is not permitted.
`
`0149-29 | 8/03/$19.00
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`Copyright © 2003 Excerpta Medica,Inc.
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`AstraZeneca Exhibit 2031 p. 1
`InnoPharmaLicensing LLC v. AstraZeneca AB
`IPR2017-00905
`Fresenius-Kabi USA LLC v. AstraZeneca AB
`IPR2017-01912
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`

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`J.ER. Robertsonet al.
`
`concentrations at 28 days were 2- to 5-fold lower than the maximum value.
`Plasma concentration data for the 250-mg dose were best described by a 2-
`compartment pharmacokinetic model, with an apparent terminal phase hali-life
`of ~49 days, beginning ~3 weeks after administration. Mean area under the
`plasma concentration—time curve for days 0 through 28 (AUC,5.) was propor-
`tional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analy-
`sis of covariance model of the pharmacokinetic data projected an estimated
`increase in AUC,5, of a factor of 1.84 (95% CI, 1.67 to 2.04).
`Conclusions: The IM formulation of fulvestrant used in this study had pre-
`dictable, dose-linear pharmacokinetics. The prolonged-release properties of this
`formulation suggested that it may be well suited for the once-monthly dosing
`schedule intended forclinical use. (Clin Ther. 2003;25:1440-1452) Copyright ©
`Excerpta Medica,Inc.
`Key words: advanced breast cancer, fulvestrant, estrogen receptor antagonist,
`antiestrogen, pharmacokinetics.
`
`INTRODUCTION
`Although tamoxifen has been a great asset in the treatment of breast cancer,!?
`some features make it less than ideal. For example, patients with advanced dis-
`ease whoinitially respond to tamoxifen may ultimately develop resistance, which
`mayresult in disease progression.** Moreover, tamoxifen treatment may increase
`the risk of developing endometrial cancer (P = 0.049).° For these reasons, there
`has been considerable interest in developing alternative hormonal treatments for
`breast cancer that improve on the success of tamoxifen.®7
`Fulvestrant’ (previously known as ICI 182,780) is an estrogen receptor (ER)
`antagonist with no known agonist effects; it works by downregulating the ER.2-!9
`This mechanism contrasts with that of tamoxifen, which acts mainly as an estro-
`gen antagonist but also has estrogen agonist properties.?!! Because fulvestrant has
`a different mode of action than tamoxifen, it has the potential to be effective
`against tamoxifen-resistant tumors; in vitro, in vivo, and clinical studies have con-
`firmed the lack ofcross-resistance.!°.!*-!4 Moreover, its pure antiestrogenic prop-
`erties should make it less likely than tamoxifen to have detrimental stimulatory
`effects on the endometrium;these results have been shown in animal studies.'°
`Following promising results from early clinical trials with fulvestrant,?'* 2
`Phase III studies!®!’ involving a total of >800 patients have been recently com-
`pleted. Results of these studies showed similar efficacy and tolerability for ful-
`vestrant 250 mg IM, once monthly, compared with the most appropriate second-
`
`“Trademark: Faslodex® (AstraZeneca Pharmaceuticals LP. Wilmington, Delaware).
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`line therapy, the third-generation aromatase inhibitor anastrozole 1 mg PO, once
`daily. 16,17
`Unlike tamoxifen—a triphenylethylene—fulvestrant is a steroidal molecule de-
`rived from estradiol with a long alkylsulphinyl side chain in the 7-alpha position
`(Figure 1). Fulvestrant’s chemical properties are such thatit is poorly soluble and
`has low and unpredictable oral bioavailability. Thus, a parenteral formulation of
`fulvestrant has been developed in an attempt to maximize delivery of the drug
`molecule.
`For therapeutic use, fulvestrant is available in a castor oil-based solution for
`IM injection that slowly releases the drug over a period of at least 1 month. The
`aim ofthis article is to describe the pharmacokinetics of 3 different single doses
`of fulvestrant (50, 125, and 250 mg).
`
`PATIENTS AND METHODS
`Study Design
`The data for this pharmacokinetic assessment were gathered during a random-
`ized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter
`trial. The primary objective of the study was to compare the antiestrogenic and
`antiproliferative properties of fulvestrant with tamoxifen and placebo. The meth-
`ods andresults pertinent to the primary objective are reported elsewhere.’® A pre-
`specified secondary objective of the study was to determine the pharmacokinetic
`profiles of single doses of fulvestrant, presented here.
`Patients with primary breast cancer awaiting curative-intent surgery were ran-
`domized to preoperative treatment with fulvestrant, tamoxifen, or placebo. Surgery
`took place 15 to 22 days after the start of drug treatment. Blood samples for phar-
`macokinetic analysis were collected up to 12 weeks aiter the start of drug treatment.
`The study was approved by the ethics committee at each center before any pa-
`tients were enrolled at that center, and was conducted in accordance with the
`
`9
`
`ON ahs
`
`o-
`
`|S
`
`Figure |. Chemical structure of the estrogen receptor antagonist fulvestrant, 7-alpha-[9-
`(4,4,5,5,5 penta fluoropentylsulphinyl) nonylJestra- | ,3,5-(10)-triene-3, | 7-beta-diol.
`
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`J.AR. Robertson et al.
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`1964 Declaration of Helsinki as amended in Hong Kong in 1989 and the
`Republic of South Africa in 1996. All patients gave written informed consent be-
`fore entering the study.
`
`Patients
`Patients were postmenopausal women with primary breast cancer (clinical
`stages T1-T3) confirmed by histology or cytology. Tumors had to be ER positive
`or of unknown ERstatus. The main exclusion criteria were metastatic disease:
`previous treatment of the tumor with hormonal therapy, chemotherapy, or radio-
`therapy; treatment with hormone replacement therapy in the previous 4 weeks;
`abnormalliver functiontests; or severe systemic disease. Patients could be with-
`drawn from the study because of adverse events or protocol violations, as well as
`at the investigator's discretion or the patient's request.
`
`Treatments
`Patients were randomized in a 1:1:1:1:1 ratio to treatment with fulvestrant (50,
`125, or 250 mg), tamoxifen (20 mg), or placebo. The placebo matchedthe ta-
`moxifen tablets to maintain blinding between tamoxifen and placebo. However,
`fulvestrant doses were not blinded. Thus, patients allocated to fulvestrant knew
`which treatment they received, whereas those allocated to tamoxifen or placebo
`did not know which of those treatments they received. Investigators were blinded
`similarly. Fulvestrant was administered as a single IM injection in the buttock 15
`to 22 days before surgery. Tamoxifen and placebo were taken PO oncedaily from
`the start of treatment until the day before surgery (ie, for 14 to 21 days).
`Patients did not receive any systemic anticancer therapies, other than the study
`medication,for the duration of the study. Estrogen replacement therapy was also
`prohibited during the study.
`
`Blood Sampling and Analysis
`Blood samples (10 mL) were drawn into heparin tubes for assay of plasma ful-
`vestrant before and at 2, 7, 10, 14, 21, 28, 35, 42, 56, and 84 days (12 weeks)
`after administration. Samples were centrifuged at 1000g for 10 minutes and the
`plasma was removed and stored at —-20°C until analysis. Plasma samples were
`packed in dry ice at -80°C andtransportedto the laboratory for pharmacokinetic
`analysis. Fulvestrant was extracted from 0.5 mL of plasma by mixing with 2.0 mL
`of hexane/propan-2-ol. Following centrifugation, the organic layer was separated
`and evaporated to dryness. The extract was reconstituted andinjected into a high-
`performance liquid chromatography (HPLC) system with an Inertsyl YMC-ODS-
`AQ 3F HPLC column (Hichrom Ltd., Berkshire, United Kingdom) coupled to a
`Sciex API Ill+ triple quadruple mass spectrometerfitted with a heated nebulizer
`interface (Applied Biosystems, Foster City, California). Fulvestrant was monitored
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`in positive multiple reaction mode using 607 m/z for the precursor ion and 589
`m/z for the product ion. Fulvestrant was quantified using a 1/x weighted linear
`least squares regression line generated from spiking standard amountsoffulves-
`trant over the concentration range 0.25 to 50.0 ng/mL. The limit of quantifica-
`tion for the assay was 0.25 ng/mL and the coefficient of variation ranged from
`7.70% to 17.1% for standards of 40.0 ng/mL and 1.0 ng/mL,respectively.
`
`Pharmacokinetic Analysis
`Maximum plasmafulvestrant concentration (C
`max)» Plasma concentration at 28
`days (C,,,,—the minimum time between doses—and time to maximum concen-
`tration (T,,,,) were determined by inspection of individual patient data. Area un-
`der the concentration-time curve in the first 28 days (AUC,,,) and AUC from
`time O to the last quantifiable plasma concentration (AUC,,) were calculated us-
`ing the linear trapezoidalrule.
`Estimates ofhalf-life (t,,.) and AUC from time 0 to infinity (AUC,_,.) were ob-
`tained from a first-order, 2-compartment, pharmacokinetic modelfitted to the
`250-mg dose data using a naive pooled data approach; that is, it was assumed
`that all plasma concentrations had come from the same patient. Thus, although
`there were concentration data from a numberofpatients at each doselevel, this
`approach did not allow for estimation of intersubject variability. Although it is
`also possible to describe the data for each dose with 1-compartment models, the
`2-compartment model was chosen as morerepresentative of the observed data at
`all 3 dose levels. More complex models were not evaluated due to the relatively
`infrequent data obtained duringtheinitial absorption phase. Data were weighted
`by the reciprocal of the concentrations as a compromise between overweighting
`low concentrations and obtaining an adequatefit to the initial data. Analysis was
`performed using the validated software package WinNonlin version 1.5 (Phar-
`sight Corporation, Mountain View, California). Model-generated parameters were
`also used to simulate the plasma concentration-time curves for comparison with
`observed data for the 50- and 125-mg dose groups.
`
`Statistical Analysis
`Descriptive statistics were calculated for pharmacokinetic parameters; for pa-
`rameters with a log-normaldistribution [AUC)., C,,,,. and C,,,], the data were
`log [base e] transformed and summarized as geometric meanswith coefficients of
`variation.
`Any center by treatment interaction was tested using an analysis of covariance
`(ANCOVA) model with center, log (dose), and the interaction as covariates, per-
`formed using the SAS procedure PROC MIXED (SAS Institute Inc., Cary, North
`Carolina). If the center by log (dose) interaction was not significant at the 1%
`level, then this was dropped from the model; subsequently, the hypothesis that
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`J.ZR. Robertsonetal.
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`each AUC,5, was proportional to the dose wastested using an ANCOVA model
`with the following factors: center, dose as a class variable, and log (dose) as a con-
`tinuousvariable. If the effect of dose as a class variable was not significant at the
`5% level, then it was assumed that the AUC could be described by a power model
`of the form AUC = a x dose?, where a is the multiplying constant and b is the
`exponential constant. A further ANCOVA model wasfitted including center and
`log (dose) as continuous variables. The coefficient b can be estimated from that
`ANCOVA model, andasignificant departure from 1 would show that AUCis not
`proportionalto dose.
`The overall size of the study population was based on a powercalculation for
`the primary end points, which included tumor markers of hormonereceptor ex-
`pression andproliferation. The size of the subset of patients included in the phar-
`macokinetic analysis was based on the power required to detect deviations from
`dose proportionality such that AUC was 50% higher or 33% lower than expected.
`Detection of such an effect with a power of 80% and a 2-sided significance level
`of 5% required 23 patients per group. To allow for nonassessable patients, the in-
`tention was to include at least 25 patients from each fulvestrant dose group in
`the pharmacokinetic analysis.
`
`RESULTS
`Patients
`A total of 200 patients entered the study, of whom 58took part in the pharmaco-
`kinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). The meanages of
`the patients who took part in the pharmacokinetic analysis were 66 years (range,
`53-82 years), 69 years (range, 59-82 years), and 65 years (range, 48-80years) in the
`fulvestrant 50-, 125-, and 250-mg groups, respectively. All patients were white. The
`treatment groups were well matched at baseline for age and hormonereceptorstatus.
`Primary efficacy and safety data from the study have been previously reported.'®
`
`Pharmacokinetics
`The pharmacokinetic parameters calculated from a noncompartmentanalysis
`for each subject are summarized in Table I. Following single IM injections of ful-
`vestrant, the T_,, ranged from 2 to 19 days (medians of 6.98, 6.98, and 6.96 days
`in the 50-, 125-, and 250-mg dose groups, respectively), with relatively shallow
`concentration-time profiles indicating a prolonged release of fulvestrant from the
`injection site (Figure 2). After the peak concentration, plasma concentrations of
`fulvestrant declined over time, and it was possible to define plasmaprofiles over
`the course of 228 days in most subjects, with the data corresponding to an ap-
`proximately log-linear profile over this time scale. At the proposed clinical dose
`interval of 28 days, C,,,, values were 2- to 5-fold lower than the C,, values (for
`patients in whom both values were measurable). However, for most patients in
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`
`Table |. Summary of pharmacokinetic parameters from a noncompartment analysis
`following a single intramuscular injection of fulvestrant 50, 125, or 250 mg.
`
`
`Fulvestrant 50 mg
`Fulvestrant {25 mg
`Fulvestrant 250 mg
`
`Gmean
`
`Cmean
`
`Gmean
`
`Parameter
`n
`(CV%)
`n
`(CV%)
`n
`(CV%)
`
`
`116.50 (25)
`20
`69.10 (G1)
`16
`32.90 (43)
`[5
`AUC,9¢.g * d/émL
`183.58 (22)
`20
`103.79 (37)
`16
`31.27 (76)
`19
`AUC,_,. ng > d/mL
`7.39 (28)
`22
`427 (68)
`16
`1.98 (64)
`20
`Cae NE/ML
`2.13 (28)
`17
`1.16 (25)
`a
`0.42 (35)
`14
`Coin N/M
`
`
`
`
`
`
`20 6.98 16 6.98 22maxi t 6.96
`
`n = number of patients; Gmean = geometric mean; CV = coefficient of variation; AUC,5, = area under the
`plasma concentration-time curve to day 28; AUC, , = AUC from time 0 to the last quantifiable plasma concen-
`tration, C,,,, = maximum plasma concentration; C,,,, = plasma concentration at day 28 (minimum time between
`doses); Tax ~ time to C..
`Given as median, rather than Gmean.
`
`© Observed
`~— Predicted
`
`
`
`
`
`ee ee ee ee eee ee eee eee Limit of
`:
`detection
`7
`120
`
`—T
`80
`
`T
`100
`
` 100 PlasmaFulvestrantConcentration(ng/mL)
`
`
`
`0.1
`
`0
`
`60
`
`—T
`20
`
`TO
`40
`
`Time (d)
`
`Figure 2. Comparison of observed plasma concentrations after a single dose of fulves-
`trant 250 mg with the predicted profile derived from a fitted model of the
`250-mg data (n = 20).
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`J.ER. Robertsonetal.
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`the fulvestrant 125- and 250-mg dose groups, it was possible to define plasma
`profiles over a muchlongerinterval, with significantlevels of fulvestrantstill mea-
`surable 84 days after administration. The decline in plasma concentrations for
`these subjects appeared to be biphasic, with evidence of a slower phase ofrelease
`between 21 and 84 days after administration. Although intersubject concentration—
`time profiles of fulvestrant were similar, mean profiles are not presented here due
`to marked intersubject differences between actual and nominal sample times and
`incomplete profiles at the lowest dose. However, pharmacokinetic modeling of
`pooled data from the 250-mg cohort was consistent with the plasma concentra-
`tion data being well described by a 2-compartment model withfirst-order input,
`as illustrated in Figure 2. A summary of the secondary pharmacokinetic parame-
`ters derived from a 2-compartment model of the 250-mg dose data with first-
`order input is given in Table II. Simulated concentration—time profiles for each
`dose level were also derived from the 250-mg dose model and are compared with
`the observed patient data in Figure 3.
`
`Dose Proportionality
`In the dose range investigated, graphical representation of AUC,,, data (Fig-
`ure 4) is consistent with the increased exposure to the drug that occurs with in-
`creasing doses. Similarly, for C_,, and C_,, (Figure 5), it can be seen that the
`dose-normalized data for fulvestrant 50, 125, and 250 mg are almost superim-
`posable, indicating dose-proportional exposure for a 5-fold increase in dose.
`AUC,_, was not assessed for evidence of dose proportionality due to the inter-
`subject differences in the time periods up to the final measurement. The
`ANCOVA model of AUC,,, found no significant effect of dose as a class variable,
`which is consistent with the effect of dose on AUC being appropriately described
`by a power model. The proportionality coefficient estimated from the model was
`
`
`
`Table Il. Summary of secondary pharmacokinetic parameters derived from a 2-
`compartment model of data on fulvestrant 250 mg, with first-order input.
`
`
`
` Parameter Estimate, Gmean (CV%)
`
`AUC,ng + dimL
`CoaneNe/ML
`nme A
`tip4
`
`255.3 (10.3)
`78 (3.5)
`5.1 (67)
`49.3 (29.7)
`
`Gmean = geometric mean; CV = coefficient of variation; AUC,., = area under the plasma concentration-time
`curve from time 0 toinfinity; C,.. = maximum plasma concentration; T,,,, = time to C,.; t, np = apparent
`terminal-phasehalf-life.
`*Given as median, rather than Gmean.
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`—— Madel 250 mg
`- Predicted 125 mg
`oe Predicted 50 mg
`@ Observed 250 mg
`A Observed 125 mg
`O Observed 50 mg
`
`(ng/mL)
`PlasmaFulvestrantConcentration
`
`
`
`Time (d)}
`
`Figure 3. Comparison of observed plasma concentrations after a single dose of fulves-
`trant 50, 125, or 250 mg (n = 19, n = 16, and n = 20, respectively) with pre-
`dicted profiles from a fitted model of the 250-mg data.
`
`0.88 (95% CI, 0.74 to 1.03). Because the 95% CI for the proportionality coeffi-
`cient includes 1, the results are consistent with AUC,,, being proportional to the
`dose. The estimated effect of doubling the dose corresponding to this proportion-
`ality coefficientis an increase in AUC,,, byafactor of 1.84 (95% CI, 1.67 to 2.04).
`
`DISCUSSION
`In this population of breast-cancer patients, the long-acting IM formulation of ful-
`vestrant provided prolonged release of the drug over several weeks. Plasmafulves-
`trant concentrations at 28 days after dosing were typically about a quarter of the
`maximum concentration, within a range of 2- to 5-fold lower, and werestill read-
`ily detectable up to 84 days after administration, particularly in the 250-mg dose
`group. This finding suggests that with monthly administration, there would be
`some accumulation of fulvestrant in the circulation. The apparentt,,. of the
`terminal-phase half-life of fulvestrant determinedin this study (49 days) was longer
`than the 14 to 19 hours previously found by 1 of the authors (M.PH.) following an
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`J.FR. Robertson et al.
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`300
`
`y°Oo
`
`d/mL) 8
`AUC2(ng:
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`Fulvestrant Dose (mg)
`
`Figure 4. Mean area under the plasma concentration-time curve in the first 28 days
`(AUC,5) after administration, and distribution of data from individual patients
`who received fulvestrant 50 mg (n = [5),fulvestrant 125 mg (n = 16), or ful-
`vestrant 250 mg (n = 20).
`
`IV injection of fulvestrant, confirming that plasma concentrations of fulvestrant af-
`ter IM injection are primarily determined by the rate of release from the injection
`site and do notreflect the elimination of the compound. The slow decline in
`plasma concentrations and the subsequently high concentrations at 28 days after
`administration are consistent with demonstratedefficacy results for once-monthly
`dosing of this formulation of fulvestrant.!>!6
`The plasma concentration data obtained for fulvestrant 250 mg were well described
`by a 2-compartment pharmacokinetic model, in which a slower terminal phase be-
`gan ~3 weeks after administration. The model generated pharmacokinetic parameters
`that were estimated with reasonable precision, and it appears to adequately describe
`concentrations obtained up to 3 monthsafter a single dose. Although the model
`adequately represented the pooled data for all the individuals and wasalso pre-
`dictive of exposure for the fulvestrant 50- and 125-mg dose groups, there was con-
`siderable variability and overlap of data, particularly in these groups, in which
`the variation was generally larger than that of the fulvestrant 250-mg dose
`group.
`Assessmentof dose proportionality was based on partial areas corresponding to
`the dose interval of 28 days and available for all patients in each dose group.
`AUC,5, was not available for patients in whom plasmalevels were below the
`level of detection before day 28. Although there was considerable intersubject
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`
`
`MeanC,,,,/dose
`
`B
`
`
`
`MeanC,,,,,/dose
`
`0.020
`0.018
`
`0.016
`
`0.014
`
`0.012
`
`0.010
`
`0,008
`
`0.006
`
`0.004
`0.002
`
`0.000
`
`0.20
`0.18
`0.16
`
`0.14
`
`0.12
`
`0.10
`
`0.08
`
`0.06
`
`0.04
`0.02
`
`0,00
`
`50
`
`100
`
`(50
`
`200
`
`250
`
`Fulvestrant Dose (mg)
`
`50
`
`100
`
`
`ae
`—
`(50
`200
`
`—>
`250
`
`Fulvestrant Dose (mg)
`
`Figure 5. Effect of dose on (A) mean plasma concentration at 28 days (C,,,)}—the mini-
`mum time between doses—and (B) mean maximum plasma concentration
`(C,among patients who received fulvestrant 50 mg (n = 14 and n = 20, re-
`spectively), fulvestrant 125 mg (n = |} and n = 16, respectively), and fulvestrant
`250 mg (n = 17 and n = 22,respectively). Bars show coefficients of variation.
`
`variation with some overlap of adjacent doses, there did not appear to be signif-
`icant departures from dose proportionality for AUC,,,, with a dose interval of
`28 days being the proposed therapeutic regimen. The prospective statistical plan
`demonstrated that a proportionality coefficient of more than +0.2519 (relative to 1)
`would need to be detected to rule out dose proportionality for the 5-fold dose
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`J.ZR. Robertsonetal.
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`range. Despite a slightly lower recruitment to the subprotocol than planned, the
`95% CI for the proportionality coefficient was narrow enough to exclude any im-
`portantdifferences from dose proportionality. C,,,, and C,.. values also appeared
`to be proportional to the dose, although this finding was not subjectto statisti-
`cal analysis. Of the 3 doses evaluated in this study, fulvestrant 250 mg resulted
`in greatest exposureto the drug; previously reported pharmacodynamic data from
`this study!® showedthatthis dose wasalso associated with the greatest reduction
`in ER expression. However, no correlation between the plasma fulvestrant con-
`centrations for individual patients and the pharmacodynamic end points was
`identified from the results of this trial.
`
`CONCLUSIONS
`The IM formulation of fulvestrant used in this study had predictable, dose-linear
`pharmacokinetics. The prolonged-release properties of this formulation resulted
`in plasma concentrations sustained over several weeks and supported the once-
`monthly dosing schedule used inclinical trials.
`
`ACKNOWLEDGMENTS
`This study was supported by AstraZeneca (Macclesfield, United Kingdom).
`The authors thank Mr. D.A. Clarke and Mr. S.A. Rhead for assistance in gen-
`erating the pharmacokinetic data, and acknowledge the contributions of Ana-
`lytico Medinet BV (Breda, the Netherlands) for performing the plasma assays and
`Michael Thompson for providing editorial assistance.
`
`REFERENCES
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`. Lykkesfeldt AE. Mechanisms of tamoxifen resistance in the treatment of advanced
`breast cancer. Acta Oncol. 1996;35(Suppl 5):9-14.
`. van. Leeuwen FE, Benraadt J, Coebergh JW, et al. Risk of endometrial cancer after
`tamoxifen treatment of breast cancer. Lancet. 1994;343:448-452.
`. Wakeling AE. The future of new pure antiestrogens in clinical breast cancer. Breast
`Cancer Res Treat. 1993;25:1-9.
`. Bajetta E, Zilembo N, Bichisao E. Aromatase inhibitors in the treatment of post-
`menopausal breast cancer. Drugs Aging. 1999;15:271-283.
`. Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182,780 (Faslodex): Develop-
`mentof a novel, “pure” antiestrogen. Cancer. 2000;89:817-825.
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`CLINICAL THERAPEUTICS®
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`9. Howell A, DeFriend DJ, Robertson JF et al. Pharmacokinetics, pharmacological and
`anti-tumoureffects of the specific anti-oestrogen ICI 182780 in women with advanced
`breast cancer. Br J Cancer 1996;74:300-308.
`10. Coopman P, Garcia M, Brunner N, et al. Anti-proliferative and anti-estrogenic effects
`of ICI 164,384 and ICI 182,780 in 4-OH-tamoxifen-resistant human breast-cancer
`cells. Int J Cancer. 1994;,56:295-300.
`1l. MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action.
`Pharmacol Rev. 1998;50:151~196.
`12. Lykkesfeldt AE, Larsen SS, Briand P Humanbreastcancer cell lines resistant to pure
`anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer. 1995;61:529-534.
`13. Hu XE Veroni M, De Luise M, et al. Circumvention of tamoxifen resistance by the
`pure anti-estrogen ICI 182,780. Int J Cancer. 1993;55:873-876.
`14. Howell A, DeFriend D, Robertson J, et al. Response to a specific antioestrogen
`(ICI 182780) in tamoxifen-resistant breast cancer. Lancet. 1995-345:29-30.
`15. Dukes M, Waterton JC, Wakeling AE. Antiuterotrophiceffects of the pure antioestrogen
`ICI 182,780 in adult female monkeys (Macaca nemestrina): Quantitative magnetic res-
`onance imaging. J Endocrinol. 1993;138:203-210.
`16. Howell A, Robertson JE Quaresma AlbanoJ, et al. Fulvestrant, formerly ICI 182,780,
`is as effective as anastrozole in postmenopausal women with advanced breast cancer
`progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-3403.
`17. Osborne CK,Pippen J, Jones SE, et al. Double-blind, randomizedtrial comparing the
`efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women
`with advanced breast cancer progressing on prior endocrine therapy: Results of a
`North Americantrial. J Clin Oncol. 2002;20:3386-3395.
`18. Robertson JE, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biolog-
`ical effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyllestra-1,3,5,
`(10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women
`with primary breast cancer. Cancer Res. 2001;61:6739-6746.
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`Address correspondenceto: John ER. Robertson, MD, FRCS, Nottingham City
`Hospital, Hucknall Road, Nottingham NG51 1PB, United Kingdom. E-mail: john.
`robertson@nottingham.ac.uk
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