`
`03 12-5963/04/0008-0529$3 1.0/0
`ORIGINAL RESEARCH ARTICLE
`© 2004 Adis Data Information BY,All rights reserved.
`
`Pharmacokinetic Profile of
`Intramuscular Fulvestrant in
`Advanced Breast Cancer
`
`John F.R. Robertson, Bjorn Erikstein? Kent C. Osborne,? John Pippen;
`Steven E. Come,° Leroy M. Parker,’ Stan Gertler,” Mike P. Harrison’ and
`David A. Clarke®
`
`1 Nottingham City Hospital, Nottingham, UK
`Radium Hospital, Oslo, Norway
`Baylor College of Medicine, Houston, Texas, USA
`Texas Oncology, Dallas, Texas, USA
`Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
`Dana-Farber Cancer Institute, Boston, Massachusetts, USA
`Ottawa Regional Cancer Center, Ottawa, Ontario, Canada
`AstraZeneca Pharmaceuticals, Macclesfield, UK
`
`ANDOWN
`
`Abstract
`
`Objective: To characterise the pharmacokinetics of a long-acting formulation of
`fulvestrant following intramuscular administration of single and multiple doses.
`Study design: Pharmacokinetic investigations of single and multiple doses of
`fulvestrant were conducted within two global phase III efficacy studies that
`compared intramuscular fulvestrant with oral anastrozole in postmenopausal
`women with hormone-sensitive advanced breast cancer (study 0020, conducted in
`Europe, Australia and South Africa, and study 0021, conducted in North
`America).
`Methods: Patients received once-monthly intramuscular injections of fulvestrant
`250mg (1 x SmL for <21 months in study 0020; 2 x 2.5mL for <30 months in
`study 0021). Serial blood samples were collected for the first 28 days after the
`initial dose and immediately prior to all subsequent monthly doses. Plasma
`fulvestrant concentrations were determined by high-performance liquid chro-
`matography-tandem mass spectrometty.
`Patients: Twenty-six (study 0020) and 193 (study 0021) postmenopausal women,
`comprising the pharmacokinetic subgroups of the phase III efficacy trials, were
`studied. Patients had shown disease progression or recurrence following previous
`hormonal therapy for advanced disease or had relapsed after adjuvant endocrine
`therapy with a nonsteroidal antiestrogen.
`Outcome measures and results: For single-dose fulvestrant 250mg, area under
`the concentration-time curve from time zero to 28 days (AUC2s8), maximum
`observed plasma concentration (Cmax), minimum observed plasma concentration
`at 28 days (Cmin) and time to maximum plasma concentration (tmax) were
`determined. For multiple-dose fulvestrant 250mg once monthly, steady-state
`trough concentrations (Ctrough) were determined. Plasma fulvestrant concentra-
`
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`530 Robertson etal.
`
`tions reached a peak at a median of 7 days (range 2-8 days) postdose, and declined
`biexponentially with a slower phase commencing approximately 2-3 weeks
`postdose. Intersubject variability in Cmax and AUC2s was approximately 6-fold
`and 4-fold, respectively. Mean parameters for single-dose fulvestrant were:
`AUC2g, 148 ug e day/L; Cmax, 8.2 ug/L; Cmin, 2.6 ug/L; tmax, 7.0 days. Geomet-
`ric mean Ctrough increased from 2.57 to 6.15 [g/L (study 0020) and from 2.38 to
`6.52 ug/L (study 0021) over the first 6 months, reaching steady-state concentra-
`tions of approximately 6—7 ug/L (study 0020) or 9 ug/L (study 0021). Preliminary
`pharmacokinetic analysis, using a naive pooled data approach, suggests that
`observed single- and multiple-dose plasma profiles can be adequately described
`with a two-compartment kinetic model. Model-generated steady-state AUC2s
`values were approximately 300 ug « day/L.
`Conclusions: The intramuscular formulation of fulvestrant displays predictable
`kinetics and approximately 2-fold accumulation on administration once monthly.
`At the proposed therapeutic dosage (250mg once monthly), plasma fulvestrant
`concentrations are maintained within a narrow range throughout the administra-
`tion interval,
`thus ensuring stable systemic drug exposure during long-term
`treatment.
`
`
`Fulvestrant (Faslodex®)!, a new estrogen recep-
`tor (ER) antagonist, is now available for the treat-
`ment of hormone receptor-positive metastatic breast
`cancer
`in
`postmenopausal women
`that
`has
`progressed during prior
`antiestrogen
`therapy.
`Fulvestrant acts by blocking ER transcriptional ac-
`tivities and downregulating cellular levels of the
`ER."3] Unlike the nonsteroidal antiestrogens (e.g.
`tamoxifen, toremifene and raloxifene), which dis-
`play mixed estrogen antagonist and agonist proper-
`ties,'**! fulvesirant causes complete abrogation of
`estrogen-sensitive gene transcription and has no
`knownestrogen agonist effect.'©! Fulvestrant has a
`unique mode of action that offers the potential for
`continued hormonal treatment in patients with ad-
`vanced, hormone-sensitive breast cancer that has
`progressed with tamoxifen treatment. The efficacy
`of fulvestrant
`in this treatment setting has been
`confirmed in a phase II clinical study, where women
`treated with fulvestrant achieved a clinical benefit
`tate of 69% after disease progression with tamoxifen
`treatment,'”! Fulvestrant also offers potential thera-
`peutic advantages over aromatase inhibitors in the
`sustained plasma drug concentrations, and will also
`postmenopausal setting as, unlike aromatase imhibi-
`
`
`tors, itis able to block the trophic effects of exoge-
`nous estrogens. In two global phase III studies car-
`ried out in postmenopausal women with advanced,
`tamoxifen-resistant breast cancer (trial 0020, con-
`ducted in Europe, South Africa and Australia, and
`trial 0021, conducted in North America), fulvestrant
`was similar to anastrozole for the primary efficacy
`endpoint, time to progression (median 5.5 vs 5.1
`months [trial 0020] and 5.4 vs 3.4 months[trial
`0021] for fulvestrant and anastrozole, respectively).
`Secondary endpoints included objective response
`rate, clinical benefit rate and median duration of
`response, which were not significantly different be-
`tween the two treatment groups.
`In both trials,
`fulvestrant and anastrozole were equally well toler-
`ated.&"1
`Fulvestrant has low aqueous solubility and has
`been developed as a long-acting, oil-based formula-
`tion for use as a once-monthly intramuscular injec-
`tion. This parenteral depot formulation provides ad-
`equate bioavailability and offers potential com-
`pliance advantages over existing breast cancer
`treatments. Intramuscular administration can offer
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`©2004 Adis Data Information BY,All rights reserved.
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`Clin Pharmacokinet 2004; 43 (8)
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`
`Fulvestrant in Breast Cancer
`
`be less affected by vomiting and subsequent tablet
`loss than oral agents. Preliminary findings in post-
`menopausal women with primary breast cancer indi-
`cate that slow-release intramuscular fulvestrant ex-
`hibits linear kinetics over the dose range 50-250mg
`following single-dose administration.“°!
`The aim of the present series of investigations,
`conducted within the confines of the phase ITclin-
`ical trial programme, was to characterise the phar-
`macokinetic profile of fulvestrant after single and
`multiple doses.
`
`suppressants, low-dose progestins or ketoconazole
`was not permitted during the studies, but continua-
`tion of existing treatment with these agents was
`allowed at the investigator’s discretion.
`The studies were approved by the relevant local
`ethics committees and were conducted in accor-
`dance with the principles of Good Clinical Practice
`and the Declaration of Helsinki. Written informed
`consent was obtained from each patient prior to
`study entry. Efficacy and tolerability findings from
`these studies are reported elsewhere.'*:”!
`
`Materials and Methods
`
`Pharmacokinetic Study Design
`
`Patients
`
`Both studies recruited postmenopausal women
`with hormone-sensitive advanced breast cancer who
`
`had experienced either disease recurrence or pro-
`eression following previous hormonal therapy for
`advanced disease or whose disease had relapsed
`following adjuvant endocrine therapy with a non-
`steroidal antiestrogen, Patients were defined as hor-
`mone sensitive if they: (1) had received =12 months
`of adjuvant hormonal therapy before relapse; (i)
`had shown 23 months of tumour remission or
`stabilisation following hormonal
`therapy; or (iii)
`were ER positive or progesterone receptor (PgR)
`positive.
`Patients who had received more than one prior
`endocrine treatment for advanced breast cancer
`
`were excluded from the studies, as were those with
`severe/uncontrolled systemic disease or hepatic im-
`pairment(total bilirubin >1.5 times the upper limit
`of normal [ULN]; alanine aminotransferase [ALT]
`or aspartate aminotransferase [AST] >2.5 times the
`ULNinthe absence of hepatic metastasis; or ALT or
`AST >5 times the ULN in the presence of hepatic
`metastasis). Patients with a history of treatment with
`fulvestrant or an aromatase inhibitor, or recent expo-
`sure to extensive radiotherapy, cytotoxic therapy,
`estrogen replacement
`therapy, any non-approved
`drug (within 4 weeks) or a luteinising hormone-
`releasing hormone (LHRH) analogue (within 3
`months) were also excluded from study participa-
`tion.
`Initiation of corticosteroids, adrenocortical
`
`European Study (0020)
`A randomised, open-label, parallel-group study,
`conducted primarily in Europe, Australia and South
`Africa, investigated the plasma kinetics of fulves-
`trant following single monthly (28 + 3 days) intra-
`muscular injections of fulvestrant 250mg, adminis-
`tered in a total volume of 5mL into the gluteus
`maximus muscle. Serial blood samples were collect-
`ed for the first 28 days of treatment and single blood
`samples were obtained before each subsequent dose,
`for a period of <21 months.
`
`North American Study (0021)
`parallel-group
`A randomised,
`double-blind,
`study conducted in North America investigated the
`plasma kinetics of
`fulvestrant
`following single
`monthly (28+3 days) intramuscular injections of
`fulvestrant 250mg, administered in two 2.5mL in-
`jections (one in each buttock). To preserve study
`blindness, matching anastrozole placebo tablets
`were supplied for once-daily oral administration.
`Serial blood samples were collected for 28 days
`after the first dose and single blood samples were
`obtained before each subsequent dose, for a period
`of <30 months,
`
`Pharmacokinetic Assessments
`
`Serial blood samples (10mL) for pharmacokine-
`tic analyses were collected predose and at 3 hours
`and(at any time) 1, 2, 7, 10, 14, 21 and 28 daysafter
`the first dose of fulvestrant. A further blood sample
`was collected 21 days after the third dose of fulves-
`
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`Robertson etal.
`
`In addition, predose
`(study 0021 only).
`trant
`(trough) blood samples (10mL) were taken immed-
`iately before each monthly fulvestrant injection for
`the duration of each study. Samples were collected
`in lithitum-heparin tubes and centrifuged for 10 min-
`utes at 1000¢ within 10-15 minutes of blood sam-
`pling. The plasma was immediately separated, fro-
`zen and stored at —20°C until required for analysis.
`
`Assay Method
`Plasma fulvestrant concentrations were deter-
`mined by means of a validated highly sensitive and
`specific high-performance liquid chromatography
`(HPLC)-tandem mass spectrometry method, using
`deuterated fulvestrant as
`the imternal
`standard.
`Fulvestrant was extracted from a 0.5mL heparinised
`plasma sample using 2mL of 10% (v/v) hexane/
`2-propanol
`and,
`following centrifugation,
`the
`organic layer was evaporated to dryness under a
`stream of nitrogen at 40°C. The dry residue was
`reconstituted in 200WL of methanol/water (5 : 1 v/v)
`and a 20uUL aliquot was injected onto a S5cm x 4mm
`Inertsil® C18 HPLC column (GL Sciences, Inc.,
`Tokyo, Japan) and eluted at a flow rate of 0.7 mL/
`min, Detection was performed with a Sciex API
`IlI+® triple quadrupole mass spectrometer (Perkin-
`Elmer, Boston, MA, USA) in positive multiple reac-
`tion mode (MRM), The following ions were select-
`ed for measurement (precursor/product transitions):
`m/z 607-589, the product ion of fulvestrant, was
`measured against that of the m/z 613-595 product
`ion of the [7H6]fulvestrant internal standard.
`Concentrations of fulvestrant were calculated.
`from peak area ratios (fulvestrant/internal standard)
`by reference to calibration series constructed by
`adding known amounts of fulvestrant (0.2550 p1g/
`L) to control plasma and extracting these standards
`in parallel with the test samples. Quantification was
`performed using a weighted (1/concentration2) least
`squares linear regression line generated from the
`standard samples. No samples with concentrations
`higher than the top standard were found, and dilu-
`tion into the working range with blank plasma was
`therefore not necessary. The performance of the
`assay was monitored throughout use by inclusion of
`quality control samples prepared at low, medium
`
`and high concentrations in blank human plasma, and
`analysed in duplicate with each batch of sample
`analysis. The acceptance/rejection criteria were
`based. upon a coefficient of variation (CV) of 20%.
`The lower limit of quantification of the assay was
`0.25 ug/L, while assay precision, expressed as the
`intra- and inter-assay coefficients of variation
`(CV%), at this level were 19.5% and 16.2%, respec-
`tively, and both generally <7% at the higher concen-
`trations (as assessed in study 0021). Accuracies
`were 97.3-109% of the theoretical concentrations
`for the three quality control standards.
`
`Pharmacokinetic Analysis
`The maximum observed plasma concentration
`(Cmax), time to reach the maximum plasma concen-
`tration (tmax) and minimum plasma concentration
`(Cmin) during the 28-day period after the first dose
`were determined from the individual plasma con-
`centration-time profiles. In the multiple-dose stud-
`ies, trough plasma concentrations (Ctrough) were de-
`termined directly from blood samples collected im-
`mediately prior to each monthly injection. The
`plasma concentration-time data for fulvestrant were
`analysed by non-compartmental methods using vali-
`dated software (WinNonlin version 1.5; Scientific
`Consulting, Cary, NC, USA). The area under the
`concentration-time curve from time zero to 28 days
`(AUC2s) [+2 days] after the first dose was calculat-
`ed using the linear trapezoidal method. Estimates of
`accumulation, time to steady state and the plasma
`elimination half-life (t,p8) were obtained usingphar-
`macokinetic models, with first-order iput and dis-
`tribution, fitted to the single-dose plasma concentra-
`tion-time data and also to the multiple-dose Ctrough
`data from each trial by using a naive pooled data
`approach (i.e.
`it was assumed that all the plasma
`concentrations came from the same patient). The
`data were analysed using WinNonlin with I/y
`weighting. Model-generated pharmacokinetic para-
`meter estimates were compared for the single and
`multiple doses.
`
`Statistical Analysis
`Data were analysed descriptively and, for para-
`meters with a log-normal distribution, Cmax, Cmin,
`Ctrough and AUC2g values were summarised as the
`
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`Fulvestrant in Breast Cancer
`
`Table |. Baseline demographic and clinical characteristics of trial
`0020 and 0021 study populations
`Characteristic
`
`Study 0020
`(n = 26)
`
`Study 0021
`(n = 193)
`
`geometric mean, CV, range and standard deviation.
`The tmax values were summarised as the median and
`the range. The geometric mean was calculated as
`exp (u) and the CV was calculated as (equation 1):
`|
`
`CV% =100 x |exp ()-1)’
`
`(Eq. 1)
`where Lt and 6? are the mean and variance ofthe
`log-transformed data.
`In those instances where
`<50% of plasma fulvestrant concentrations were
`non-quantifiable at a given timepoint, the geometric
`mean and CV were calculated by substituting the
`limit of quantification (0.25 g/L) for the missing
`values. If >50% of plasma concentrations were non-
`quantifiable,
`the geometric mean and CV values
`were reported as unknown.
`
`Results
`
`Patient Demographics
`
`The baseline demographic and clinical character-
`istics of the two study populations are summarised
`in table I. Plasma samples for determination of the
`single-dose kinetic profile of fulvestrant were ob-
`tained from 16 of 222 patients randomised to receive
`the drug in study 0020 and from four of 206 patients
`who received the drug in study 0021. However, in
`view of the limited size of this latter patient cohort,
`single-dose data are given for indicative purposes
`only. Trough plasma samples for determination of
`the multiple-dose kinetic profile were obtained from
`26 and 193 patients in studies 0020 and 0021, re-
`spectively. Both study cohorts had a mean age of 63
`years and mean bodyweights were similar: 69ke and
`72kg for studies 0020 and 0021, respectively. The
`majority of patients were Caucasian, although the
`North American cohort included 10% Black and 4%
`Hispanic patients.
`
`Single-Dose Pharmacokinetics
`
`Following the first dose of intramuscular fulves-
`trant, the time needed to achieve peak plasma con-
`centrations indicated prolonged release of fulves-
`trant from the injection site (tmax generally varying
`
`85.5
`9.8
`
`4]
`0.5
`
`86.5
`6.7
`6.7
`
`46.1
`43.5
`10.4
`
`47.7
`31.6
`63.2
`
`8.3
`50.3
`415
`
`Age at entry (years)*
`mean (SD)
`median
`
`range
`Weight at baseline (kg)?
`mean (SD)
`median
`
`range
`Race (%)
`White
`Black
`
`Hispanic
`other
`
`62.9 (10.0)
`61
`
`63.2 (11.2)
`64
`
`43-85
`
`33-89
`
`68.1 (9.8)
`69.0
`
`40.9-81.2
`
`71.2 (14.2)
`72A
`
`39.5-126.8
`
`100
`0
`
`0
`0
`
`Hormonereceptor status (%)
`84.6
`ER+ and/or PgR+
`0
`ER-and/or PgR->
`15.4
`ER and PgR status unknown
`WHOperformance status at baseline (%)
`0
`46.2
`1
`50.0
`2
`3.8
`
`Local regional radiotherapy (%)
`Radiotherapy for metastasis (%)
`Cytotoxic chemotherapy (%)
`Adjuvant hormonaltreatment (%)
`yes (<12 months to relapse)
`yes (212 months to relapse)
`no
`
`73.1
`19.2
`38.5
`
`3.8
`42.3
`53.8
`
`Hormonal treatment for advanced breast cancer (%)
`51.8
`yes (remission for 23 months)
`65.4
`2.6
`yes (remission for <3 months)
`0
`
`no 45.6 34.6
`
`a Data for n = 25 and n = 188, respectively.
`b
`ER negative and PgR negative, or ER negative and PgR
`unknown, or ER unknown and PgR negative.
`ER = estrogen receptor; PgR = progesterone receptor.
`
`between 2 and 8 days). Thereafter, the concentra-
`
`tions declined slowly to about a quarter of the maxi-
`mum by 28 days after administration. Individual
`
`plasma concentration-time profiles demonstrated
`some interpatient variability in trial 0020; Cmax and
`AUC2 values ranged from 3.8 to 23.8 ug/L and 73
`to 309 ug « day/L, respectively, in studies 0020 and
`
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`Robertson etal.
`
`Table Il. Single-dose pharmacokinetic parameters for fulvestrant
`after an initial intramuscular dose of fulvestrant 250mg in postmen-
`opausal women with advanced breast cancer. Data are expressed
`as geometric mean (CV%) [n], except where indicated
`Parameter and unit
`Study 0020
`Study 0021
`Cmax (ug/L)
`8.20 (63.8) [16]
`4.76 (68.1) [4]
`Cmin (ug/L)
`2.62 (33.4) [14]
`2.38 (47.7) [131]
`tmax (days)?
`6.97 (1.86-7.95) [15]
`8.8 (6.97-12.0)[4]
`
`148 (45.3) [13]
`88.4 (47.3)[4]
`AUCa8 (ug @ day/L)
`a Median (range) [n]
`AUC2g = area under plasma concentration-time curve from time
`zero to day 28; Cmax = maximum plasma concentration; Cmin =
`minimum plasma concentration; CV% = coefficient of variation;
`tmax = time to Cmax.
`
`0021. Mean pharmacokinetic parameters, derived
`from individual patients, are summarised in table IT.
`Because the differences between the actual and
`nominal sampling times of individual patients, a
`mean plasma concentration-time profile was not
`constructed. However, the data were adequately de-
`scribed by fitting a two-compartment pharmacokin-
`etic model, with first-order input, to a naive pool of
`all individual points. The relationship between the
`observed concentrations and the model-predicted
`profile is illustrated in figure 1. Primary and secon-
`
`100 5
`
`dary parameter estimates are given in table III. It
`was also possible to describe the single-dose data
`with a one-compartment model. However,
`it was
`found that this model under-predicted multiple-dose
`concentrations as a result of the slow terminal phase
`known to occur beyond 21 days."°
`
`Multiple-Dose Pharmacokinetics
`
`Repeated monthly intramuscular administration
`of fulvestrant 250mginitially resulted in progressive
`increases iN Ctrough. In trials 0020 and 0021, respec-
`tively,
`the geometric mean Ctrough after the first
`injection was 2.6 and 2.4 ue/L, gradually increasing
`to 6.5 and 6.2 ug/L and approximating to steady
`state after the sixth dose. Although there was some
`interpatient variation (typical CV 30-40%), individ-
`ual patient and mean Crrough values subsequently
`exhibited minimal fluctuation during both trials, in-
`dicating an absence of any time-dependent changes
`during long-term administration (figure 2).
`The two-compartment disposition model derived
`previously from single-dose data, with first-order
`input and distribution rate constants, was used. to
`provide the initial estimates for a fit of the pooled
`
`Observed
`O
`— Predicted
`
`
`
`
`
`Concentration(ug/L)
`
`
`
` 0
`
`7
`
`14
`
`21
`
`28
`
`35
`
`0.1
`
`Time (days)
`Fig. 1. Comparison of observed plasma fulvestrant concentrations with the predicted profile derived from a fitted model of the pooled data
`following the first intramuscular dose of fulvestrant 250mg (study 0020).
`
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`
`Fulvestrant in Breast Cancer 535
`
`TableIll. Model parameters and derived pharmacokinetic data for the first dose of fulvestrant during once-monthly intramuscular adminis-
`tration of fulvestrant 250mg in postmenopausal women with advanced breast cancer. Values in parentheses are CV%
`Parameter and unit
`Study 0020 (n = 28)
`Study 0021 (n = 131)
`Apparent total clearance (L/h)
`31 (4.7)
`31 (3)
`Apparent volume of central compartment (L)
`14 000 (38)
`13 000 (150)
`Apparent absorption rate constant (day-')
`0.385 (48)
`0.28 (158)
`Apparent volume of second compartment (L)
`32 000 (22)
`39 000 (108)
`Distributional clearance (L/h)
`46 (40)
`73 (60)
`Disposition half-life (days)
`51 (26)
`57 (8.3)
`AUC. (ug @ day/L)
`369 (4.1)
`333 (3.0)
`Cmax (ug/L)
`11.8 (6.6)
`8.3 (8.8)
`
`tmax (days) 4.6 (11.2) 4.2 (8.3)
`
`AUC. = area under the plasma concentration-time curve from time zero to infinity; Cmax = maximum plasma concentration; CV% =
`coefficient of variation; tmax = timeto Cmax.
`
`individual multiple-dose data. The resulting fitted
`profiles illustrate the relationship between thefitted.
`profile and the actual plasma concentration-time
`data (figure 3). The use of a two-compartment
`model, based on parameter estimates taken from a
`previous single-dose trial of intramuscular fulves-
`trant 50-250me¢,"" provided an adequate fit for the
`data generated following the first injection, and was
`successfully extended to fit
`the multiple-dose
`Ctrough data. The two-compartment, model-generat-
`ed pharmacokinetic parameter estimates (transfer
`and elimination rate constants and volume of the
`central compartment) for the multiple-dose data
`were similar (within 20%) to those for the single-
`dose data. These were estimated with better preci-
`sion, as the trough samples provide additional infor-
`mation on the slower terminal phase (AUCg, repre-
`senting approximately 60% of the total AUC). Thus,
`the two-compartment pharmacokinetic model was
`considered suitable to describe exposure to fulves-
`trant following both single and multiple doses. The
`model appears to adequately describe the Ctrough
`values observed in patients from both studies for up
`to 2.5 years after the first dose and, thus, indicates
`linearity of fulvestrant pharmacokinetics during re-
`peated administration. Steady-state plasma fulves-
`trant exposures (AUCsgs), predicted according to the
`structural model, were very similar in both studies
`(294 and 336 Use e day/L fortrials 0020 and 0021,
`respectively). By comparison with the single-dose
`data, AUCss represented an approximate 2-fold ac-
`cumulation.
`
`There was no evidence of a change in the phar-
`macokinetic behaviour of fulvestrant compared with
`that following the first injection, and it was possible
`to predict
`the multiple-dose pharmacokinetics of
`fulvestrant by using modelling techniques. Plasma
`concentrations of fulvestrant were maintained with-
`in a narrow range throughoutthe assessmentperiod,
`consistent with
`the
`linearity
`of
`fulvestrant
`pharmacokinetics during repeated administration
`over a prolonged period.
`
`Discussion
`
`As shown in previous investigative studies in
`patients with breast cancer,'”! the present longer-
`term studies confirm that fulvestrant
`is released
`
`slowly into the systemic circulation after intramus-
`cular administration of the long-acting formulation
`and that plasma concentrations are maintained at
`detectable levels over the 4-week administration
`interval. The pharmacokinetics of fulvestrant, when
`administered as an intramuscular injection, are cha-
`racterised by a narrow plasma concentration range
`(approximately 3-fold) maintained throughout the
`administration interval and an apparently long typ
`(40-60 days). Thelatter is reflected in the relatively
`long time to reach steady state following repeated
`administration (3-6 months). However, it should be
`noted that although accumulation does occur (ap-
`proximately 2- to 3-fold),
`the majority of this is
`achieved after three doses.
`
`© 2004 Adis Data Information BY.All rights reserved,
`
`Clin Pharmacokinet 2004; 43 (8)
`
`AstraZeneca Exhibit 2060 p. 7
`
`
`
`Robertson etal.
`
`
`
`
`
`A
`
`Study 0020
`Study 0021
`
`_
`
`a
`
`a
`~
`
`
`
`-
`a =
`
`
`
`
`
`
`
`
`
`
`
`
`+
`_
`r
`w
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lak
`
`
`= a
`—_
`a x a
`ae
`
`
`A
`= @ tf
`
`
`
`1005
`
`2mo
`=e
`S
`@
`9
`5
`6
`
`107
`
`
`
`a =
`
`
`
`1
`
`0
`
`T
`2
`
`T
`4
`
`T
`6
`
`T
`8
`
`T
`10
`
`T
`12
`
`T
`14
`
`T
`16
`
`T
`18
`
`T
`20
`
`T
`22
`
`1
`24
`
`Time (mo)
`Fig. 2. Geometric mean (+ SD) trough plasma fulvestrant concentrations during once-monthly intramuscular administration of fulvestrant
`250mgin studies 0020 and 0021.
`
`the
`As with many slow-release preparations,
`pharmacokinetics of
`long-acting
`intramuscular
`fulvestrant are controlled by its slow systemic rfe-
`lease, and therefore its intrinsic elimination charac-
`teristics cannot be assessed directly. Single-dose
`data from volunteer studies using an intravenous
`formulation indicate that
`fulvestrant
`is
`rapidly
`cleared from the circulation with a well defined tp
`of approximately 14~18 hours." For the long-act-
`ing intramuscular formulation, the apparent long typ
`indicates that drug release is much slower than elim-
`ination. The resulting plasma profile can therefore
`be considered to reflect the rate of drug absorption;
`the overall elimination rate constant ke approxi-
`mates to the absorption rate constant ka."?7! Thus,
`although alterations in clearance rate (e.g. due to
`hepatic or renal impairment or drug interactions)
`might affect overall systemic exposure (AUC) on
`repeated administration, minimal immediate effects
`on the plasma profile would be expected.
`Earlier indications of modest drug accumulation
`occurring during once-monthly intramuscular ad-
`ministration of long-acting fulvestrant 250mg"!
`were confirmed in the present studies, with Ctrough
`(predose) approximately doubling between the first
`and sixth doses as steady state was approached.
`
`Intrapatient variation was minimal in those patients
`where numbers of sequential trough samples were
`obtained, even though the interindividual variability
`was maintained.
`
`The aim of these pharmacokinetic analyses was
`to investigate the consistency of the concentration
`data from subsequent doses of fulvestrant with the
`more extensive data from the first administration, as
`a diagnostic of appreciable change in the underlying
`pharmacokinetics, and not
`the identification of
`covariates that could explain individual variation.
`The naive pooled data approach ignores individual
`differences and, consequently, the method does not
`differentiate interindividual variability from in-
`traindividual variability. Given the large number of
`potentially confounding variables
`(age, weight,
`pathophysiological changes, activity, etc.), the para-
`meter estimates using the naive pooled data ap-
`proach are usually considered poorer than those
`provided by rigorous two-stage or nonlinear mixed
`effects modelling approaches. However, by using
`the substantial body of single-dose profiles and con-
`tinuous multiple trough data from larger numbers, a
`satisfactory exploratory model has been provided,
`which appears to describe the observed data over a
`prolonged period of administration.
`
`©2004 Adis Data Information BY,All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (8)
`
`AstraZeneca Exhibit 2060 p. 8
`
`
`
`Fulvestrant in Breast Cancer
`
`Despite the decreasing numbers of patients at
`later timepoints, the good fit of the observed trough
`plasma data with the two-compartment model over
`multiple dose cycles indicates that
`there was no
`appreciable modification in the kinetics of fulves-
`trant during long-term administration (up to 2.5
`years). This consistency is further supported by the
`close similarity in model-generated estimates of
`steady-state plasma fulvestrant exposure in the two
`
`phase ITI studies. Therefore, the increase in plasma
`concentration that occurs with multiple doses seems
`predictable and appears to be solely due to the slow-
`release characteristics of this formulation rather than
`
`to any change in pharmacokinetic behaviour.
`The pharmacokinetics of the long-acting intra-
`muscular formulation of fulvestrant have previously
`been reported to be unaffected by the method of
`administration (either as 2 x 2.5mL or 1 x 5mL),
`
`a
`
`100
`
`©
`
`Observed
`
`— Predicted
`
`aB
`
`S 105
`=
`5
`c
`q
`2
`4
`S
`4
`=
`4
`oD
`2°°
`oO
`
`1a
`q
`
`
`
`
`
`
`
`1
`1
`:
`1
`;
`;
`'
`
`0.1
`
`b
`100 5
`
`a |
`SD
`=A
`=
`<
`2
`S&S
`<
`8
`2
`5
`o
`
`QO
`\da
`dj
`9
`Q
`os
`& gS
`AUN
`VEN
`lalale\iWoe RV
`
`ARERR ASEAR OBO Gy OO
`JIQARE e
`ny
`e
`4SIQW OR KORO e
`Oo
`9
`NAY ry ie
`wy
`=| a 5
`Y
`7REES ¥
`Oe
`TAS ¥—,40
`Yo00
`O86
`148
`40
`
`J
`
`Q
`
`0.1
`
`0
`
`1
`3
`
`7
`6
`
`‘
`9
`
`'
`12
`
`;
`15
`
`;
`18
`
`'
`21
`
`‘
`24
`
`‘
`27
`
`30
`
`33
`
`Time (mo)
`Fig. 3. Comparison of the observed plasma fulvestrant concentrations with predicted multiple-dose profiles derived from a fitted model of
`n of fulvestrant 250mg in studies 0020 (a) and 0021 (b).
`the pooled data following once-monthly intramuscular administratio!
`
`©2004 Adis Data Information BY,All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (8)
`
`AstraZeneca Exhibit 2060 p. 9
`
`
`
`Robertson etal.
`
`with the two regimens providing virtually superim-
`posable plasmaprofiles after the first dose.""“! The
`present study showsthat repeated administration of
`1 x SmL and 2 x 2.5mL injections of fulvestrant
`250mg are equally effective in maintaining plasma
`concentrations in an empirically defined therapeutic
`range (that
`is, plasma fulvestrant concentrations
`generally reached in treatment schedules associated
`with efficacy) for at least 30 months. It therefore
`seems reasonable to conclude that these regimens
`may be used interchangeably, depending on which
`is considered more convenient in a particular clin-
`ical setting.
`
`Conclusion
`
`ICI 182,780 (Fas-
`2. Howell A, Osborne CK, Morris C, et al.
`lodex™): development of a novel ‘pure’ antiestrogen. Cancer
`2000; 89: 817-25
`
`3. Curran M, Wiseman L. Fulvestrant. Drugs 2001; 61: 807-13
`4. Jordan VC, Murphy CS. Endocrine pharmacology of anties-
`trogens as antitumour agents. Endocr Rev 1990; 11: 578-610
`
`5. MacGregor JI, Jordan VC. Basic guide to the mechanisms of
`antiestrogen action. Pharmacol Rev 1998; 50: 151-96
`6. Wakeling AE, Dukes M, Bowler J. A potent specific pure
`antiestrogen with clinical potential. Cancer Res 1991; 51:
`3867-73
`
`7. Howell A, DeFriend DJ, Robertson JF, et al. Pharmacokinetics,
`pharmacological and anti-tumour effects of the specific anti-
`oestrogen ICI 182780 in women with advanced breast cancer.
`Br J Cancer 1996; 74: 300-8
`
`8. Howell A, Robertson JER, Quaresma Albano J, et al. Fulves-
`trant (formerly ICI 182,780) is as effective as anastrozole in
`postmenopausal women with advanced breast cancer progress-
`ing after prior endocrine treatment. J Clin Oncol 2002; 20:
`3396-403
`
`9. Osborne CK,Pippen J, Jones SE,et al. A double-blind, random-
`ized trial comparing the efficacy and tolerability of fulvestrant
`versus anastrozole in post-menopausal women with advanced
`breast cancer progressing on prior endocrine therapy: results of
`a North American trial. J Clin Oncol 2002; 20: 3386-95
`
`10. Robertson J, Nicholson R, Gee J, et al. The pharmacokinetics of
`single-dose Faslodex™ (ICI 182,780) in post-menopausal pri-
`mar