Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer

Robertson, J. F. R.; Erikstein, Bjørn; Osborne, Kent; Pippen, John; Come, Steven E.; Parker, Leroy M.; Gertler, S.; Harrison, M.; Clarke, D.

doi:10.2165/00003088-200443080-00003

Cited by 83 publications

(51 citation statements)

References 6 publications

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“…The greater effect of fulvestrant 500 mg on Ki67, ER, and PgR at 4 weeks may be at least partly attributable to the loading element of the fulvestrant 500 mg regimen, since steady-state plasma levels should have been reached at 4 weeks, whereas steady-state levels would not have been reached with fulvestrant 250 mg at this time [10].…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Kuter

Gee

Hegg

et al. 2012

Breast Cancer Res Treat

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NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

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Section: Discussionmentioning

confidence: 99%

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Kuter

Gee

Hegg

et al. 2012

Breast Cancer Res Treat

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“…1B, 85.9 Ϯ 8.6% increase in neuronal viability compared with ␤-amyloid 1-42 alonetreated cultures; ‫,ءء‬ P Ͻ 0.01). Based on these analyses, we selected 50 ng/ml (82.4 nM), a relatively low and clinically relevant concentration of ICI 182,780 (Howell et al, 1996;Robertson et al, 2004), for subsequent comparative analyses of the impact of ICI 182,780 on the molecular mechanisms underlying estrogen-inducible neurotrophism and neuroprotection Although the full spectrum of molecular mechanisms that underlie estrogen promotion of neuronal plasticity and survival remains to be elucidated, a number of cellular responses have been well documented . Key among these is 17␤-estradiol regulation of intracellular Ca 2ϩ signaling .…”

Section: Ici 182780 Promoted Neuronal Survival Against Neurodegeneramentioning

confidence: 99%

Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science Understanding of Estrogen Signaling and Development of Estrogen Modulators with a Dual Therapeutic Profile

Zhao

O’Neill

Brinton

2006

J Pharmacol Exp Ther

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The present study sought to determine the characteristics of ICI 182,780 (Faslodex) action in rat primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against neurodegenerative insults associated with Alzheimer's disease and related disorders. Dose-response analyses revealed that ICI 182,780, in a concentration-dependent manner, significantly promoted neuron survival following exposure to either excitotoxic glutamate (200 M)-or ␤-amyloid 1-42 (1.5 M)-induced neurodegeneration of hippocampal neurons. At a clinically relevant concentration of 50 ng/ml, ICI 182,780 exerted nearly maximal neuroprotection against both insults with efficacy comparable with that induced by the endogenous estrogen 17␤-estradiol. Thereafter, we investigated the impact of 50 ng/ml ICI 182,780 on mechanisms of 17␤-estradiol-inducible neuronal plasticity and neuroprotection. Results of these analyses demonstrated that ICI 182,780 directly induced a series of rapid intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) oscillations in a pattern comparable with that of 17␤-estradiol. In addition, ICI 182,780 exerted dual regulation of the glutamateinduced rise in [Ca 2ϩ ] i identical to that induced by 17␤-estradiol. Further analyses demonstrated that ICI 182,780 induced significant activation of extracellular signal-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expression of spinophilin and Bcl-2, with efficacy comparable with neurons treated with 17␤-estradiol. Taken together, results of these in vitro analyses of ICI 182,780 provide direct evidence of an estrogenic agonist profile of ICI 182,780 action in rat hippocampal neurons. Therapeutic development of neuroselective estrogen receptor modulators that mimic ICI 182,780 is discussed with respect to the potential of safe and efficacious alternatives to estrogen therapy for the prevention of postmenopausal cognitive decline and late-onset Alzheimer's disease.

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“…Across reviewed trials, the standard dose and schedule reported for fulvestrant was a single 250 mg IM injection, [59] and a pharmacokinetic analysis of Trial 0020 and Trial 0021 [60], comparing between the different modes of injection, found no evidence of pharmacokinetic or tolerability difference suggesting a similar clinical efficacy, although these studies were not likely powered or designed to evaluate efficacy. Contrary to the Std schedule, a loading dose (LD) schedule was employed in the EFECT trial [20] as well as in several ongoing Phase III trials ( [23] have suggested that patients with hormonereceptor-positive tumours benefit more so than patients with non-receptor-positive tumours.…”

Section: Discussionmentioning

confidence: 99%

Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review

Flemming

Madarnas

Franék

2008

Breast Cancer Res Treat

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A systematic review was undertaken to examine all available evidence to develop and support clinical recommendations regarding the use of fulvestrant (Faslodex((R))) as systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women. MEDLINE, EMBASE, American Society of Clinical Oncology Annual Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library were searched through to April of 2008 for reports of randomized controlled trials that met established inclusion criteria. Four relevant Phase III trials were available for inclusion based on established criteria. Three of four Phase III superiority trials found no significant difference between fulvestrant and control, either anastrozole or exemestane, across efficacy and safety endpoints following prior endocrine therapy failure, with two trials further confirming non-inferiority of fulvestrant to anastrozole retrospectively. Fulvestrant can therefore be considered as alternative therapy to anastrozole or exemestane in postmenopausal women with locally advanced or metastatic breast cancer that has recurred on prior adjuvant endocrine therapy or progressed on prior endocrine therapy for advanced disease. There are, however, important methodological concerns across reviewed trials that should be taken under consideration as they may limit the strength of such a conclusion.

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Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer

Cited by 83 publications

References 6 publications

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science Understanding of Estrogen Signaling and Development of Estrogen Modulators with a Dual Therapeutic Profile

Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review

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