Pharmacokinetics of a Single Dose
`of Fulvestrant Prolonged-Release Intramuscular
`lniection 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 P. Harrison, BSC5
`
`1Nottingham City Hospital, Nottingham, 2Belfast City Hospital, Belfast, 3Royal Liverpool
`University Hospital, Liverpool, "Royal Hallamshire Hospital, Sheflield, 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 l/ll 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 (2O 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—pea1< 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.
`
`0|49-29|8/03/$|9.00
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`j.F.R. Robertson Ea: af
`
`concentrations at 28 days were 2- to 5—fold lower than the maximum value.
`Plasma concentration data for the 250—mg dose were bes.t described by a 2-
`compartment pharrnacokinetic model, with an apparent terminal phase half—life
`of ~49 days, beginning ~3 weeks after administration. Mean area under the
`plasma concentration—time curve for days 0 through 28 (AUC0_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 prolongedrelease properties of this
`formulation suggested that it may be well suited for the once-monthly dosing
`schedule intended for clinical use. (Clin Ther 2003;25:1440~1452) 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}-2
`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 = O.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‘10
`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.1942'” 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~” 2
`Phase III studiesmi” 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-
`
`“frademarlc Faslodex® (AstraZeneca Pharmaceuticals LR Wilmington, Delaware).
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`CLINICAL THERAPEUT|CS®
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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). Fulvestrants 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, p1acebo—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-alpha-[9-
`(4,4,5,5,5 penta fluoropentylsulphinyl) nony|]estra-|,3,5—(|0)-triene-3,|7-beta-diol.
`
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`].F.R. Robertson er al.
`
`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 121211121 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 1M 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 hexane/propan—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 Ltd., 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 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 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 1.0 ng/mL, respectively.
`
`Pharmacaldnetic 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 (AUCH8) and AUC from
`time 0 to the last quantifiable plasma concentration (AUC04) were calculated us-
`ing the linear trapezoidal rule.
`Estimates of half—life (tm) and AUC from time 0 to infinity (AUC04) 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—coInpartment 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 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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`}.F.R. Robertson et al.
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`each AUCM8 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 = a X dosel’, 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.“3
`
`Pharmacokinetics
`
`The pharmacokinetic parameters calculated from a noncompartment analysis
`for each subject are summarized in Table 1. Following single 1M 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, Cm,“ 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 I. Summary of pharmacokinetic parameters from a noncompartment analysis
`following a single intramuscular injection of fulvestrant 50, I25, or 250 mg.
`
`Fulvestrant 50 mg
`
`Fulvestrant
`
`I 25 mg
`
`Fulvestrant 250 mg
`
`Parameter
`
`AUC0_28, ng ~ d/mL
`AUCO_t. ng - d/mL
`Cm“, rig/mL
`CW, ng/mL
`Tmax, d‘
`
`n
`
`I5
`I9
`20
`I4
`20
`
`Gmean
`
`(CV%)
`
`32.90 (43)
`3|.27 (76)
`I98 (64)
`0.42 (35)
`6.98
`
`n
`
`I6
`I6
`I6
`I
`I
`I6
`
`Gmean
`
`(CV%)
`
`69.IO (SI)
`I037‘? (37)
`427 (68)
`H6 (25)
`6.98
`
`n
`
`20
`20
`22
`I7
`22
`
`Gmean
`
`(CV%)
`
`I I650 (25)
`I83.58 (22)
`7.39 (28)
`2. I 3 (28)
`6.96
`
`n = number of patients; Gmean = geometric mean; CV I coefficient of variation; AUCH8
`plasma concentration—time curve to day 28; AUCM = AUC from time 0 to the last quantifiable plasma cohcen—
`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.
`
`= area under the
`
`I00
`
`0 Observed
`‘“— Predicted
`
` _
`
`_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Limit of
`detection
`
`_
`
`
`
`PlasmaFulvestrantConcentration(ng/mL)
`
`
`
`
`
`0-‘
`
`0
`
`‘T
`20
`
`7-
`40
`
`-1
`80
`
`r—
`I00
`
`*1
`I20
`
`60
`
`Time (cl)
`
`Figure 2. Comparison of observed plasma concentrations after a single dose of fu|ves-
`trant 250 mg with the predicted profile derived from a fitted model of the
`
`250-mg data (:1 = 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 AUC0_28 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.
`AUCO_[ 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
`
`AUCOA”. ng - d/mL
`Cmax, ng/mL
`TW,d*
`rm, d
`
`Estimate, Gmean (CV%)
`
`255.3 (|0.3)
`7.8 (3.5)
`5.i
`(6.7)
`49.3 (29.7)
`
`Gmean = geometric mean; CV = coefficient of variation; AUCWN 2 area under the plasma concentration—time
`curve from time 0 to infinity; Cmax = maximum plasma concentration: Tmax = time to Cm‘; tl/25 = apparent
`terminal-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 = I9, n = I6, 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 AUCO_28 being proportional to the
`dose. The estimated effect of doubling the dose corresponding to this proportion-
`ality coefficient is an increase in AUCO_28 by a factor of l .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 fu1ves—
`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 tmfi of the
`terminal-phase half-life of fulvestrant determined in this study (49 days) was longer
`than the l4 to 19 hours previously found by l of the authors (M.P.I-I.) following an
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`J.F.R. Robertson et all
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`300
`
`B’o
`
`(Hg' §
`AUCo_23
`
`0
`
`50
`
`I00
`
`I50
`
`200
`
`250
`
`Fulvestrant Dose (mg)
`
`Figure 4. Mean area under the plasma concentration—time curve in the first 28 days
`(AUCH8) after administration, and distribution of data from individual patients
`who received fulvestrant 50 mg (n = I5), fulvestrant I25 mg (n = I6), or fu|~
`
`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 phatmacokinetic 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 THERAPEUTlCS®
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`A 0.020
`0.0 I 8
`
`50
`
`| 00
`
`*f
`I 50
`
`*—y
`200
`
`1
`250
`
`Fulvestrantz Dose (mg)
`
`
`
`MeanCm“,/dose
`
`B
`
`
`
`MeanCm/dose
`
`0.0 I 6
`
`0.0 I4
`
`0.0 I 2
`
`00:0
`
`0008
`
`0.006
`
`0.004
`
`0.002
`
`0.000
`
`0.20
`
`0. a a
`
`0. I6
`
`0.14
`
`0. I2
`
`0. I 0
`
`0.08
`
`0.06
`
`0.04
`
`0.02
`
`0.00
`
`50
`
`I00
`
`I50
`
`100
`
`250
`
`Fulvestrant Dose (mg)
`
`Figure 5. Effect of dose on (A) mean plasma concentration at 28 days (Cmm)———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-
`spectively),fu|vestrant 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 closes, there did not appear to be signif-
`icant departures from dose proportionality for AUC0_28, with a dose interval of
`28 days being the proposed therapeutic regimen. The prospective statistical plan
`demonstrated that a proportionality coefficient of more than 20.2519 (relative to 1)
`would need to be detected to rule out dose 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. Cmx 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 studylg 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 NG5l 1PB, United Kingdom. E—mai1: john.
`robertson@nottingham.ac.ul<
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