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Matthew P. Goetz - One of the best experts on this subject based on the ideXlab platform.
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First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017Co-Authors: Matthew P. Goetz, Stephanie L. Safgren, Joel M. Reid, Mary J. Kuffel, Vera J. Suman, Sarah A. Buhrow, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Renee M. McgovernAbstract:Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-Endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received Endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and Endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-Endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.
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Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.
Endocrinology, 2017Co-Authors: Anne Gingery, Malayannan Subramaniam, Kevin S. Pitel, James N. Ingle, Russell T. Turner, Urszula T. Iwaniec, Joel M. Reid, Renee M. Mcgovern, Ronald J. Marler, Matthew P. GoetzAbstract:Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively characterize the impact of Endoxifen on the skeleton and uterus. Our results demonstrate that Endoxifen elicits beneficial effects on bone in ovary-intact rats and protects against bone loss following ovariectomy. Endoxifen is also shown to reduce bone turnover in both ovary-intact and ovariectomized rats at the cellular and biochemical levels. With regard to the uterus, Endoxifen decreased uterine weight but maintained luminal epithelial cell height in ovariectomized animals. Within luminal epithelial cells, Endoxifen resulted in differential effects on the expression levels of estrogen receptors α and β as well as multiple other genes previously implicated in regulating epithelial cell proliferation and hypertrophy. These studies analyze the impact of extended Endoxifen exposure on both bone and uterus using a Food and Drug Administration-recommended animal model. Although Endoxifen is a more potent breast cancer agent than tamoxifen, the results of the present study demonstrate that Endoxifen does not induce bone loss in ovary-intact rats and that it elicits partial agonistic effects on the uterus and skeleton in ovariectomized animals.
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The Effects of a Novel Hormonal Breast Cancer Therapy, Endoxifen, on the Mouse Skeleton
PloS one, 2014Co-Authors: Anne Gingery, Malayannan Subramaniam, Kevin S. Pitel, Jordan M. Reese, Muzaffer Cicek, Laurence B. Lindenmaier, James N. Ingle, Matthew P. Goetz, Russell T. Turner, Urszula T. IwaniecAbstract:Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, Endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and Endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of Endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day Endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and Endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from Endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, Endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of Endoxifen on bone and our results demonstrate that Endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.
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Comparative Uterotrophic Effects of Endoxifen and Tamoxifen in Ovariectomized Sprague-Dawley Rats
Toxicologic pathology, 2014Co-Authors: Karen Schweikart, Matthew P. Goetz, Sandy Eldridge, Stephanie L. Safgren, Toufan Parman, Joel M. Reid, Matthew M. Ames, Myrtle DavisAbstract:Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated Endoxifen using a classic uterotrophic effects method. Rats were given Endoxifen or tamoxifen orally for 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-fold higher in the estradiol group than in the tamoxifen or Endoxifen groups, which did not differ from vehicle controls. Tamoxifen and Endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and Endoxifen produced an increase in the stromal BrdU labeling index (LI) that was ≤ estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that Endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that Endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the Endoxifen risk/benefit ratio may be superior to tamoxifen.
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Cellular responses to vehicle and Endoxifen treatment.
2014Co-Authors: Anne Gingery, Malayannan Subramaniam, Kevin S. Pitel, Jordan M. Reese, Muzaffer Cicek, Laurence B. Lindenmaier, James N. Ingle, Matthew P. Goetz, Russell T. Turner, Urszula T. IwaniecAbstract:A. Real-time PCR analysis of alkaline phosphatase (AP), osterix (OX), Runx2 (RX2), estrogen receptor α (ERα) and estrogen receptor β (ERβ) in adherent marrow stromal cells derived from Endoxifen treated mice relative to vehicle treated control animals. B. Real-time PCR analysis of AP, OX, and RX2 following 24 hour treatment of human fetal osteoblast cells expressing ERα (FOB/ER9) with 100 nM or 1000 nM levels of Endoxifen. C. Real-time PCR analysis of AP, OX, RX2, ERα, ERβ, matrix extracellular phosphoglycoprotein (MEPE), phosphate-regulated neutral endopeptidase (PHEX) and dentin matrix acidic phosphoprotein1 (DMP1) in cortical shells isolated from Endoxifen treated mice relative to vehicle treated control animals. D. Quantification of TRAP positive osteoclasts (OC) after MCSF and RANKL treatment of non-adherent bone marrow cells isolated from vehicle (Veh) or Endoxifen (End) treated mice. E. A representative image of differentiated osteoclasts from vehicle and Endoxifen treated mice. F. RT-PCR analysis of the osteoclast marker genes NFATc1, RANK, c-Fms and CathK, as well as the inhibitory OCIL gene, in mature osteoclasts derived from Endoxifen treated animals relative to vehicle treated controls. The mean ± SE are depicted. * denotes significance at P
Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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A multi-gram-scale stereoselective synthesis of Z-Endoxifen
Bioorganic & medicinal chemistry letters, 2018Co-Authors: Lech-gustav Milroy, Jos H. Beijnen, Nynke G L Jager, Bartjan Koning, Daphne S. Van Scheppingen, Jan Koek, Luc BrunsveldAbstract:Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-Endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-Endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration.
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Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-Endoxifen Serum Levels for Therapeutic Drug Monitoring.
Therapeutic drug monitoring, 2017Co-Authors: Sven De Krou, Hilde Rosing, Bastiaan Nuijen, Jan H.m. Schellens, Jos H. BeijnenAbstract:Background:Z-Endoxifen (further referred to as Endoxifen, unless stated otherwise) is proposed as the most important metabolite of tamoxifen. Patients receiving adjuvant tamoxifen treatment with Endoxifen levels below the threshold of 5.9 ng/mL may have an increased risk of breast cancer recurrence.
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Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and Endoxifen
British journal of clinical pharmacology, 2014Co-Authors: Rob Ter Heine, Jos H. Beijnen, Lisette Binkhorst, Ron H J Mathijssen, Anne Joy M. De Graan, Peter De Bruijn, Alwin D. R. HuitemaAbstract:Aims Tamoxifen is considered a pro-drug of its active metabolite Endoxifen. The major metabolic enzymes involved in Endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences Endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and Endoxifen. Methods We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Results Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in Endoxifen formation (inter-individual variability reduced from 55% to 25%). Conclusions We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to Endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
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Use of dried blood spots for the determination of serum concentrations of tamoxifen and Endoxifen
Breast cancer research and treatment, 2014Co-Authors: Nynke G L Jager, Hilde Rosing, Jan H.m. Schellens, Jos H. Beijnen, Sabine C. LinnAbstract:The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-Endoxifen, and a minimum therapeutic threshold for (Z)-Endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-Endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-Endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-Endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice.
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Importance of highly selective LC–MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on Endoxifen and 4-hydroxytamoxifen
Breast cancer research and treatment, 2012Co-Authors: Nynke G L Jager, Hilde Rosing, Jan H.m. Schellens, Sabine C. Linn, Jos H. BeijnenAbstract:The antiestrogenic effect of tamoxifen is mainly attributable to the active metabolites Endoxifen and 4-hydroxytamoxifen. This effect is assumed to be concentration-dependent and therefore quantitative analysis of tamoxifen and metabolites for clinical studies and therapeutic drug monitoring is increasing. We investigated the large discrepancies in reported mean Endoxifen and 4-hydroxytamoxifen concentrations. Two published LC–MS/MS methods are used to analyse a set of 75 serum samples from patients treated with tamoxifen. The method from Teunissen et al. (J Chrom B, 879:1677–1685, 2011) separates Endoxifen and 4-hydroxytamoxifen from other tamoxifen metabolites with similar masses and fragmentation patterns. The second method, published by Gjerde et al. (J Chrom A, 1082:6–14, 2005) however lacks selectivity, resulting in a factor 2–3 overestimation of the Endoxifen and 4-hydroxytamoxifen levels, respectively. We emphasize the use of highly selective LC–MS/MS methods for the quantification of tamoxifen and its metabolites in biological samples.
Vincent O. Dezentjé - One of the best experts on this subject based on the ideXlab platform.
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Exposure–response analysis of Endoxifen serum concentrations in early-breast cancer
Cancer Chemotherapy and Pharmacology, 2020Co-Authors: Anabel Beatriz Sanchez-spitman, Vincent O. Dezentjé, Hans Gelderblom, Dirk Jan Ar Moes, Jesse J. Swen, Patrick Neven, Diether Lambrechts, Henk-jan GuchelaarAbstract:Purpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of Endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three Endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine Endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen. Methods Data from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the Endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed. Results None of the thresholds showed a statistically significant difference in relapse-free survival: 5.2 ng/ml threshold: hazard ratio (HR): 2.545, 95% confidence interval (CI) 0.912–7.096, p value: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421–1.258, p value: 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR): 0.971 (95% CI 0.923–1.021, p value: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961–1.053, p value: 0.798) with Endoxifen concentrations. Conclusion Our findings do not confirm the Endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy.
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Exposure-response analysis of Endoxifen serum concentrations in early-breast cancer.
Cancer chemotherapy and pharmacology, 2020Co-Authors: A.b. Sanchez-spitman, Vincent O. Dezentjé, Hans Gelderblom, Dirk Jan Ar Moes, Jesse J. Swen, Patrick Neven, Diether Lambrechts, Henk-jan GuchelaarAbstract:PURPOSE Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of Endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three Endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine Endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen. METHODS Data from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the Endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed. RESULTS None of the thresholds showed a statistically significant difference in relapse-free survival: 5.2 ng/ml threshold: hazard ratio (HR): 2.545, 95% confidence interval (CI) 0.912-7.096, p value: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421-1.258, p value: 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR): 0.971 (95% CI 0.923-1.021, p value: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961-1.053, p value: 0.798) with Endoxifen concentrations. CONCLUSION Our findings do not confirm the Endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy.
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A prospective study on the effect of Endoxifen concentration and CYP2D6 phenotypes on clinical outcome in early stage breast cancer patients receiving adjuvant tamoxifen.
Journal of Clinical Oncology, 2018Co-Authors: A.b. Sanchez-spitman, Vincent O. Dezentjé, Carolien H. Smorenburg, Dirk Jan Ar Moes, Erdogan Batman, Jesse J. Swen, Lynn Jongen, Maartje Los, Patrick Neven, Hans GelderblomAbstract:523Background: It has been postulated that Endoxifen levels are better predictors of tamoxifen efficacy than CYP2D6 phenotype. Although in a retrospective study an Endoxifen threshold of 5.9 ng/ml ...
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CYP2D6 genotype- and Endoxifen-guided tamoxifen dose escalation increases Endoxifen serum concentrations without increasing side effects
Breast cancer research and treatment, 2015Co-Authors: Vincent O. Dezentjé, Frans L. Opdam, Hans Gelderblom, J Hartigh Den, T. Van Der Straaten, R. Vree, E. Maartense, Carolien H. Smorenburg, Hein Putter, A S DieudonnéAbstract:Breast cancer patients with absent or reduced CYP2D6 activity and consequently low Endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective Endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual’s Endoxifen level at baseline relative to the average Endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased Endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased Endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean Endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the Endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and Endoxifen-guided tamoxifen dose escalation increased Endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.
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Effect of PK-guided tamoxifen dose escalation on Endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.
Journal of Clinical Oncology, 2013Co-Authors: Frans L. Opdam, Vincent O. Dezentjé, T. Van Der Straaten, R. Vree, E. Maartense, Jan Den Hartigh, Henk-jan Guchelaar, Trees Hessing, Erdogan Batman, Carolien H. SmorenburgAbstract:595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite Endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase Endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s Endoxifen level divided by the median Endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased Endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased Endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and Endoxifen guided tamoxifen dose escalation increased Endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.
Carolien H. Smorenburg - One of the best experts on this subject based on the ideXlab platform.
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A prospective study on the effect of Endoxifen concentration and CYP2D6 phenotypes on clinical outcome in early stage breast cancer patients receiving adjuvant tamoxifen.
Journal of Clinical Oncology, 2018Co-Authors: A.b. Sanchez-spitman, Vincent O. Dezentjé, Carolien H. Smorenburg, Dirk Jan Ar Moes, Erdogan Batman, Jesse J. Swen, Lynn Jongen, Maartje Los, Patrick Neven, Hans GelderblomAbstract:523Background: It has been postulated that Endoxifen levels are better predictors of tamoxifen efficacy than CYP2D6 phenotype. Although in a retrospective study an Endoxifen threshold of 5.9 ng/ml ...
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CYP2D6 genotype- and Endoxifen-guided tamoxifen dose escalation increases Endoxifen serum concentrations without increasing side effects
Breast cancer research and treatment, 2015Co-Authors: Vincent O. Dezentjé, Frans L. Opdam, Hans Gelderblom, J Hartigh Den, T. Van Der Straaten, R. Vree, E. Maartense, Carolien H. Smorenburg, Hein Putter, A S DieudonnéAbstract:Breast cancer patients with absent or reduced CYP2D6 activity and consequently low Endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective Endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual’s Endoxifen level at baseline relative to the average Endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased Endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased Endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean Endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the Endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and Endoxifen-guided tamoxifen dose escalation increased Endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.
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Effect of PK-guided tamoxifen dose escalation on Endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.
Journal of Clinical Oncology, 2013Co-Authors: Frans L. Opdam, Vincent O. Dezentjé, T. Van Der Straaten, R. Vree, E. Maartense, Jan Den Hartigh, Henk-jan Guchelaar, Trees Hessing, Erdogan Batman, Carolien H. SmorenburgAbstract:595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite Endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase Endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s Endoxifen level divided by the median Endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased Endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased Endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and Endoxifen guided tamoxifen dose escalation increased Endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.
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Effect of PK-guided tamoxifen dose escalation on Endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.
Journal of Clinical Oncology, 2013Co-Authors: Frans L. Opdam, Vincent O. Dezentjé, T. Van Der Straaten, R. Vree, Henk-jan Guchelaar, Erdogan Batman, Trees J. Hessing, E. Maartense, Jan Den Hartigh, Carolien H. SmorenburgAbstract:595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite Endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase Endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s Endoxifen level divided by the median Endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen ...
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The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum Endoxifen levels
Cancer chemotherapy and pharmacology, 2012Co-Authors: Frans L. Opdam, Vincent O. Dezentjé, Hans Gelderblom, Carolien H. Smorenburg, J. Hartigh, A. S. Modak, J. W. R. Nortier, Erdogan Batman, R. Vree, Henk-jan GuchelaarAbstract:Purpose Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen Endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in Endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the 13C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state Endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen.
Imran Ahmad - One of the best experts on this subject based on the ideXlab platform.
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Orally administered Endoxifen inhibits tumor growth in melanoma-bearing mice
Cellular & Molecular Biology Letters, 2018Co-Authors: Paul Chen, Ateeq Ahmad, Shoukath M. Ali, Moghis U. Ahmad, Saifuddin Sheikh, Imran AhmadAbstract:Endoxifen, an active metabolite of tamoxifen, has been shown to be an effective anti-estrogenic agent in estrogen receptor-positive breast cancer patients. In melanoma, estrogen receptor expression is shown to be associated with disease progression. However, the therapeutic benefit of Endoxifen in melanoma has not yet been evaluated. Here, we present the first demonstration of the anti-melanogenic activity of Endoxifen in vitro and in vivo. The in vitro cytotoxic effect of Endoxifen was tested using a cell viability assay. The in vivo anti-melanogenic activity was evaluated in B16F10 cell-bearing C57BL/6 mice, a mouse melanoma model. The general toxicity was tested in Swiss albino mice. Endoxifen exhibited greater activity against melanoma cell lines. Treatment of B16F10 mouse and SK-MEL-5 human melanoma cell lines with 10 μM of Endoxifen for 48 h respectively resulted in 93.6 and 92.5% cell death. Orally administered Endoxifen, at dose levels of 4 and 8 mg/kg body weight/day for 20 consecutive days, respectively reduced metastatic melanoma nodules in the lungs by 26.7 and 82.7%. Endoxifen was found to be a safe and effective anti-melanogenic agent in animal studies.
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Endoxifen for breast cancer: Multiple-dose, dose-escalation study characterizing pharmacokinetics and safety in metastatic breast cancer patients.
Journal of Clinical Oncology, 2012Co-Authors: Ateeq Ahmad, Saifuddin Sheikh, Prashant Kale, R. C. Rane, Rajnish Nagarkar, Jitendra Singh, S. Krishnan, S.m. Shrivastav, P. Shetty, Imran AhmadAbstract:3089^ Background: Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. To be clinically effective, tamoxifen must be converted to Endoxifen by CYP2D6. Dire...
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First-in-human study evaluating safety and pharmacokinetics of Endoxifen, a potent estrogen-receptor antagonist for breast cancer.
Journal of Clinical Oncology, 2010Co-Authors: Ateeq Ahmad, Saifuddin Sheikh, Prashant Kale, S. Shahabuddin, R. C. Rane, Imran AhmadAbstract:3087 Background: Endoxifen is an active metabolite of tamoxifen, a widely used breast cancer drug. Treatment of breast cancer directly with Endoxifen may eliminate tamoxifen metabolism associated variability and avoid a potential serious drug-drug interaction. In this study, the safety, tolerability, and pharmacokinetics (PK) of Endoxifen at escalating single doses were assessed in healthy, adult, male and female human subjects. Methods: An open label, single oral dose, randomized, dose escalating parallel study was conducted in 40 healthy male and female fasting subjects. Eight subjects received a single dose of 0.5, 1, 2, or 4 mg Endoxifen tablets. Tamoxifen (Nolvadex) 20 mg tablets were administered to eight subjects as reference. Blood samples were collected at predose and up to 528 hours postdose for PK. Results: Single oral dose of Endoxifen at 0.5, 1, 2, or 4 mg was safe and well tolerated. Adverse events were not found and no clinically significant changes in laboratory or other safety variables w...
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Orally administered Endoxifen is a new therapeutic agent for breast cancer.
Breast cancer research and treatment, 2010Co-Authors: Ateeq Ahmad, Shoukath M. Ali, Moghis U. Ahmad, Saifuddin Sheikh, Imran AhmadAbstract:Endoxifen is the key active metabolite of tamoxifen, a widely used breast cancer drug. Orally administered tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially Endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize tamoxifen to varying degree and may not receive the optimal benefit from tamoxifen treatment. We show that oral administration of Endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of Endoxifen may avoid a potential serious drug interaction found between tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered Endoxifen is rapidly absorbed and systemically available when tested in female rats. The Endoxifen-treated rats showed 787% higher exposure (AUC(0-infinity)) and 1,500% higher concentration (C (max)) levels of Endoxifen when compared with tamoxifen. Oral Endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on Endoxifen as a potentially new therapeutic agent for breast cancer.