`of Fulvestrant Prolonged-Release Intramuscular
`Injection in Postmenopausal Women Awaiting
`Surgery for Primary Breast Cancer
`
`john ER. Robertson, MD, FRCS,1 William Odling-Smee, MD, FRCS,2
`Chris Holcombe, MD, FRCS,3 Stanley R. Kohlhardt, MD, FRCS,“ and
`Mike I’. Harrison, BSc5
`
`1Nottingham City Hospital, Nottingham, 2Belfast City Hospital, Belfast, 3Royal Liverpool
`University Hospital, Liverpool, "Royal Hallamshire Hospital, Slieflield, and 5AstraZeneca,
`Macclesfield, United Kingdom
`
`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-
`release IM formulation.
`
`Methods: Pharmacokinetic data were obtained in a randomized, partially
`blinded, placebo-controlled, parallel—group, Phase I/II multicenter trial involving
`postmenopausal women with primary breast cancer (clinical stages T1—T3, with
`tumors that were ER positive or of unknown ER status) 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). Treatment started 2 to
`3 weeks before surgery and blood was taken at various times up to 12 weeks af-
`ter fulvestrant administration to assess pharmacokinetic variables.
`Results: A total of 200 patients entered the trial, 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-mg dose 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—peal< 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.
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`O|49—Z9|8/O3/$|9.00
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`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 half—life
`of ~49 clays, beginning ~3 weeks after administration. Mean area under the
`plasma concentration—time curve for days 0 through 28 (AUCO_28) was propor-
`tional for fulvestrant 50, 125, and 250 mg. For a doubling of the close, an analy-
`sis of covariance model of the pharmacokinetic data projected an estimated
`increase in AUCO_28 of a factor of 1.84 (95% Cl, 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 for clinical use. (Clin Ther 2003;25:l440~1452) 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 who initially respond to tamoxifen may ultimately develop resistance, which
`may result in disease progression.” Moreover, tamoxifen treatment may increase
`the risk of developing endometrial cancer (P = 0.O49).5 For these reasons, there
`has been considerable interest in developing alternative hormonal treatments for
`breast cancer that improve on the success of tamoxifen.“
`Fulvestrant* (previously known as ICI 182,780) is an estrogen receptor (ER)
`antagonist with no known agonist effects; it works by downregulating the ER.8‘1°
`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 of cross-resistance.1042'” 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,9~1“ 2
`Phase III studieslér” 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 1M, once monthly, compared with the most appropriate second-
`
`llrademarkt Fasl0dex® (Astrazeneca Pharmaceuticals LP, Wilmington, Delaware).
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`CLINICAL THERAPEUTICSQ)
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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 that it 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 of this 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 and results 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 after 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
`
`
`
`Figure I. Chemical structure of the estrogen receptor antagonist fulvestrant, 7-a|pha-[9-
`(4,4,5,5,5 penta fluoropentylsulphinyl) nony|]estra-|,3,5-(I0)-triene-3,l7-beta-diol.
`
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`].F.R. 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 ER status. 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;
`abnormal liver function tests; or severe systemic disease. Patients could be with-
`drawn from the study because of adverse events or protocol violations, as well as
`at the investigators discretion or the patients request.
`
`Treatments
`
`Patients were randomized in a 1:1:1:1:l ratio to treatment with fulvestrant (50,
`125, or 250 mg), tamoxifen (20 mg), or placebo. The placebo matched the 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 once daily 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 and transported to the laboratory for pharmacokinetic
`analysis. Fulvestrant was extracted from 0.5 mL of plasma by mixing with 2.0 ml.
`of hexanejpropan-2-ol. Following centrifugation, the organic layer was separated
`and evaporated to dryness. The extract was reconstituted and injected into a high
`performance liquid chromatography (HPLC) system with an lnertsyl YMC—ODS-
`AQ 3F HPLC column (Hichrom 1.td., Berkshire, United Kingdom) coupled to a
`Sciex API 111+ triple quadruple mass spectrometer fitted with a heated nebulizer
`interface (Applied Biosystems, Foster City, California). Fulvestrant was monitored
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`CLINICAL THERAPEUTICS®
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`in positive multiple reaction mode using 607 rn/z for the precursor ion and 589
`m/z for the product ion. Fulvestrant was quantified using a l/>< weighted linear
`least squares regression line generated from spiking standard amounts of fulves—
`trant over the concentration range 0.25 to 500 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 l.0 ng/mL, respectively.
`
`Pharmacokinetic Analysis
`Maximum plasma fulvestrant concentration (Cmax), plasma concentration at 28
`days (Cmm)——the minimum time between doses——and time to maximum concen-
`tration (Tmaxl were determined by inspection of individual patient data. Area un-
`der the concentration-time curve in the first 28 days (AUCO_28) and AUC from
`time 0 to the last quantifiable plasma concentration (AUC0_[) were calculated us-
`ing the linear trapezoidal rule.
`Estimates of half—life (tm) and AUC from time 0 to infinity (AUC0_m) were ob-
`tained from a first-order, 2-compartment, pharmacokinetic model fitted 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 number of patients at each dose level, 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 more representative of the observed data at
`all 3 dose levels. More complex models were not evaluated due to the relatively
`infrequent data obtained during the initial absorption phase. Data were weighted
`by the reciprocal of the concentrations as a compromise between overweighting
`low concentrations and obtaining an adequate fit 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—normal distribution [AUC0_28, Cmax, and Cmm], the data were
`log [base 6] transformed and summarized as geometric means with 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 lnc., 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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`each AUC0_28 was proportional to the dose was tested using an ANCOVA model
`with the following factors: center, dose as a class variable, and log (dose) as a con-
`tinuous variable. 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 = Cl X dose”, where a is the multiplying constant and b is the
`exponential constant. A further ANCOVA model was fitted including center and
`log (dose) as continuous variables. The coefficient b can be estimated from that
`ANCOVA model, and a significant departure from 1 would show that AUC is not
`proportional to dose.
`The overall size of the study population was based on a power calculation for
`the primary end points, which included tumor markers of hormone receptor ex-
`pression and proliferation. 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 58 took part in the pharmaco-
`kinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). The mean ages 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, 48-80 years) 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 hormone receptor status.
`Primary efficacy and safety data from the study have been previously reported.”
`
`Phannacokinetics
`
`The pharmacokinetic parameters calculated from a noncompartment analysis
`for each subject are summarized in Table 1. Following single IM injections of ful-
`vestrant, the Tmax 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 plasma profiles 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, Cmm values were 2- to 5-fold lower than the Cmax values (for
`patients in whom both values were measurable). However, for most patients in
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`Table l. Summary of pharmacokinetic parameters from a noncompartment analysis
`following a single intramuscular injection of fulvestrant 50, I25, or 250 mg.
`
`Fulvestrant 50 mg
`
`Fulvestrant l 25 mg
`
`Fulvestrant 250 mg
`
`Parameter
`
`AUCO_28, ng ~ d/mL
`AUCW ng - d/mL
`Cm“, ng/mL
`CW, ng/mL
`Tmax, d‘
`
`n
`
`I5
`I9
`20
`I4
`20
`
`Gmean
`
`(CV%)
`
`3290 (43)
`3 l .27 (76)
`I98 (64)
`0.42 (35)
`6.98
`
`n
`
`I6
`I6
`I6
`l
`I
`I 6
`
`Gmean
`
`(CV%)
`
`69.lO (5 l)
`I037‘? (37)
`427 (68)
`|.l6 (25)
`6.98
`
`n
`
`20
`20
`22
`I7
`22
`
`Gmean
`
`(CV%)
`
`I l6.5O (25)
`l83.58 (22)
`7.39 (28)
`2. I 3 (28)
`6.96
`
`n = number of patients; Gmean = geometric mean; CV I coefficient of variation; AUQH8 = area under the
`plasma concentration—time curve to day 28; AUCO4 = AUC from time 0 to the last quantifiable plasma concen—
`tration; Cmax = maximum plasma concentration; Cm = plasma concentration at day 28 (minimum time between
`max
`doses); T
`= time to Cmax.
`‘Given as median, rather than Gmean.
`
`I00
`
`0 Observed
`“‘— Predicted
`
`
`
`detection
`
`0- '
`
`0
`
`—r
`20
`
`"l_"_
`40
`
`60
`
`—i
`80
`
`r—
`I 00
`
`*1
`I 20
`
`Time (d)
`
`
`
`PlasmaFulvestrantConcentration(ng/mL)
`
`
`
`
`
`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.F.R. Robertson et al.
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`the fulvestrant 125- and 250-mg dose groups, it was possible to define plasma
`profiles over a much longer interval, with significant levels of fulvestrant still mea-
`surable 84 days after administration. The decline in plasma concentrations for
`these subjects appeared to be biphasic, with evidence of a slower phase of release
`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 with first-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 11. 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 AUC048 data (Fig—
`ure 4) is consistent with the increased exposure to the drug that occurs with in-
`creasing doses. Similarly, for Cmax and Cmm (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.
`AUC0_t 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 AUC0_28 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 II. Summary of secondary pharmacokinetic parameters derived from a 2-
`compartment model of data on fulvestrant 250 mg, with first-order input.
`
`Parameter
`
`AUC5wdng-dhnL
`Cmax, ng/mL
`Tmax,d*
`tl/2'3, d
`
`Estimate, Gmean (CV%)
`
`2533(|O3)
`7.8 (3.5)
`5.i (6.7)
`49.3 (29.7)
`
`Gmean = geometric mean; CV = coefficient of variation; AUCW“ = area under the plasma concentration—time
`curve from time 0 to infinity; Cmax = maximum plasma concentration; Tmax = time to Cmx; tl/15 = apparent
`termina|—phase half-life.
`‘Given as median, rather than Gmean.
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`—- Model 250 mg
`- Predicted I25 mg
`» Predicted 50 mg
`----
`0 Observed 250 mg
`A Observed I25 mg
`0 Observed 50 mg
`
`
`
`PlasmaFulvestrantConcentration(ng/mL)
`
`
`
`
`
`Figure 3. Comparison of observed plasma concentrations after a single dose of fulves-
`trant 50, I25, or 250 mg (n = l9, n = l6, and n = 20, respectively) with pre-
`
`dicted profiles from a fitted model of the 250-mg data.
`
`0.88 (95% Cl, 0.74 to 1.03). Because the 95% CI for the proportionality coeffi-
`cient includes 1, the results are consistent with AUC0_28 being proportional to the
`close. The estimated effect of doubling the dose corresponding to this proportion-
`ality coefficient is an increase in AUCO_28 by a factor of 1.84 (95% Cl, 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. Plasma fulves—
`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 were still 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 apparent t1/23 of the
`terminal-phase half—life of fulvestrant determined in this study (49 days) was longer
`than the 14 to 19 hours previously found by 1 of the authors (M.P.H.) following an
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`300
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`J.F.R. Robertson et all
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`200
`
`(ng-d/mL)
`AUCo_23
`
`I00
`
`0
`
`50
`
`I 00
`
`l 50
`
`200
`
`250
`
`Fulvestrant Dose (mg)
`
`Figure 4. Mean area under the plasma concentration—time curve in the first 28 days
`
`(AUCo_28) after administration, and distribution of data from individual patients
`who received fulvestrant 50 mg (n = I5), fulvestrant I25 mg (n = I6), 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 not reflect the elimination of the compound. The slow decline in
`plasma concentrations and the subsequently high concentrations at 28 days after
`administration are consistent with demonstrated efficacy results for once-monthly
`dosing of this formulation of fulvestrant.15’16
`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 months after a single dose. Although the model
`adequately represented the pooled data for all the individuals and was also 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.
`
`Assessment of dose proportionality was based on partial areas corresponding to
`the dose interval of 28 days and available for all patients in each dose group.
`AUC0_28 was not available for patients in whom plasma levels were below the
`level of detection before day 28. Although there was considerable intersubject
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`CLINICAL THERAPEUTICS®
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`A 0.020
`0.0 I 8
`
`
`
`MeanCm“,/dose
`
`B
`
`
`
`MeanCm/dose
`
`on I 6
`
`o.o I4
`
`o.o I 2
`
`0.0I0
`
`0.008
`
`0.006
`
`0.004
`0.002
`
`0.000
`
`0.20
`0. I 8
`0. I6
`
`0. I 4
`
`0. I 2
`
`0. I 0
`
`0.08
`
`0.06
`
`0.04
`0.02
`
`0.00
`
`50
`
`I00
`
`I 50
`
`200
`
`250
`
`Fulvestrant Dose (mg)
`
`so
`
`I00
`
`~,—
`I50
`
`,—
`200
`
`~——1
`250
`
`Fulvestrant Dose (mg)
`
`Figure 5. Effect of dose on (A) mean plasma concentration at 28 days (Cmin)-—-the mini-
`mum time between doses——and (B) mean maximum plasma concentration
`
`(Cm) among patients who received fulvestrant 50 mg (n = I4 and n = 20, re-
`spectiveIy).fuIvestrant I25 mg (n = I
`I and n = I6, respectively), and fulvestrant
`250 mg (n = I7 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 AUC0_28, with a close interval of
`28 days being the proposed therapeutic regimen. The prospective statistical plan
`demonstrated that a proportionality coefficient of more than :().2519 (relative to 1)
`would need to be detected to rule out close proportionality for the 5-fold dose
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`j.F.R. Robertson et al.
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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-
`portant differences from close proportionality. Cmax and Cmm values also appeared
`to be proportional to the dose, although this finding was not subject to statisti-
`cal analysis. Of the 3 doses evaluated in this study, fulvestrant 250 mg resulted
`in greatest exposure to the drug; previously reported pharmacodynamic data from
`this study” showed that this dose was also 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 1M 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 in clinical 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.
`
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`Address correspondence to: 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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