scholarly journals The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)‐Endoxifen in Breast Cancer

2019 ◽  
Vol 13 (2) ◽  
pp. 284-292 ◽  
Author(s):  
Jeanine Marie Nardin ◽  
Werner Schroth ◽  
Thais Abreu Almeida ◽  
Thomas Mürdter ◽  
Solane Picolotto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Active Metabolite ◽  
Plasma Concentrations

Abstract P2-11-12: The influences of adherence to tamoxifen and CYP2D6 pharmacogenetics on plasma concentrations of the active metabolite (Z)-endoxifen in breast cancer

2020 ◽  
Author(s):  
Jose Claudio Casali da Rocha ◽  
Jeanine M Nardin ◽  
Werner Schroth ◽  
Thais A Almeida ◽  
Thomas Mürdter ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Active Metabolite ◽  
Plasma Concentrations

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

scholarly journals Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 278
Author(s):  
Jennifer Lagoutte-Renosi ◽  
Bernard Royer ◽  
Vahideh Rabani ◽  
Siamak Davani
Keyword(s):  
Active Metabolite ◽  
Plasma Concentrations ◽  
Antiplatelet Agent ◽  
High Plasma ◽  
Therapeutic Drug ◽  
Routine Practice ◽  
Daily Routine ◽  
Limit Of Quantification ◽  
Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

Influence of Anthropometric Characteristics in Patients With Her2-Positive Breast Cancer on Initial Plasma Concentrations of Trastuzumab

2017 ◽  
Vol 51 (11) ◽  
pp. 976-980 ◽  
Author(s):  
Jonathan González García ◽  
Fernando Gutiérrez Nicolás ◽  
Gloria Julia Nazco Casariego ◽  
José Norberto Batista López ◽  
Isaac Ceballos Lenza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Standard Dose ◽  
Plasma Concentrations ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Initial Plasma ◽  
Anthropometric Characteristics ◽  
Secondary Objective ◽  
Positive Breast Cancer

Background: Plasma concentrations of trastuzumab <20 µg/mL in patients with gastric cancer are associated with reduced progression-free and overall survival. In breast cancer treatment, this relationship has not yet been studied, but a suboptimal pharmacodynamic exposure to trastuzumab could be a reason for therapeutic failure of treatment of HER2-positive breast cancer. Objective: The objective of the present study was to determine the proportion of nonmetastatic HER2-positive breast cancers that do not reach a minimum plasma concentration ( Cmin) of 20 µg/mL after first drug administration, established as therapeutically effective in clinical trials. The secondary objective was to identify the physiological and anthropometric characteristics that determine interindividual pharmacokinetic variability. Methods: Serum concentrations of trastuzumab were assessed by ELISA on day 1 of the second cycle before administration of the second dose ( Cmin). Results: Of 19 patients included, 9 (47.4%) had a mean Cmin of 19.0 µg/mL (±12.1) after the first administration. Body mass index (BMI) and weight was the main variable that determined the achievement of therapeutic levels after the first administration. Thus, the proportion of patients reaching the target concentration was 89% when BMI was ≤30 kg/m2 but only 11% when BMI was >30 kg/m2 ( P < 0.01). Conclusions: The standard dose of 600 mg subcutaneous trastuzumab did not ensure adequate pharmacodynamic exposure from the first administration in 52% of patients, with weight and BMI being related to the plasma levels obtained.

Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1044-1044
Author(s):  
Erica Michelle Stringer-Reasor ◽  
Barbara Jane O'Brien ◽  
Ariel Topletz-Erickson ◽  
Jason B White ◽  
Mina Lobbous ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Leptomeningeal Metastasis ◽  
Newly Diagnosed ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Her2 Breast Cancer ◽  
Metastatic Setting

1044 Background: Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine for patients with metastatic HER2+ breast cancer (MBC) who have received ≥1 prior HER2-based regimen in the metastatic setting, including patients with brain metastases (BM). TBCRC049 (NCT03501979) is an investigator-initiated phase 2 single-arm study currently enrolling to evaluate the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly diagnosed LM. Here, we report the pre-specified pharmacokinetic (PK) analysis for the first 15 patients to determine bioavailability of tucatinib and its predominant metabolite, ONT-993, in the CSF. Methods: Eligible patients included adults with HER2+ MBC, KPS > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM were allowed. The primary endpoint is overall survival with an accrual goal of 30 pts. Parallel PK samples were collected in plasma and CSF via Ommaya reservoir on day 1 of cycles 1 and 2 at 0h (baseline), 2-3h, 5-7h and 24h (optional) following initiation of tucatinib 300 mg BID. Tucatinib and ONT-993 were quantified in plasma (n=15) and CSF (n=13) using validated liquid chromatography-mass spectrometry methods. Results: Tucatinib and ONT-993 plasma concentrations were consistent with previous studies and exhibited high interindividual variability. Tucatinib and ONT-993 were detectable in the CSF within 2 hours post tucatinib administration; concentrations ranged from 0.57 to 25 ng/mL for tucatinib (IC50 for tucatinib against HER2 is 3.3 ng/mL) and 0.28 to 4.7 ng/mL for ONT-993. Tucatinib concentrations in the CSF per timepoint were in a similar range to unbound plasma (plasmaub) tucatinib. CSF to plasmaub ratios were generally consistent over time; the steady-state (cycle 2) median tucatinib CSF to plasmaub ratio was 0.83 (0.19 to 2.1). ONT-993 CSF to plasmaub ratios were similar to tucatinib CSF to plasmaub ratios. Conclusions: In patients with LM from HER2+MBC who were treated with tucatinib, trastuzumab, and capecitabine, tucatinib and ONT-993 were detectable in the CSF of all patients at median levels similar to plasmaub tucatinib. This is the first documented evidence of tucatinib distributing into the CSF in patients with HER2+MBC. Efficacy and safety of tucatinib, trastuzumab, and capecitabine in patients with HER2+ LM will be reported upon completion of TBCRC 049 accrual. Clinical trial information: NCT03501979 .

scholarly journals P1533 Early evaluation of global longitudinal strain and biomarkers at initiation of trastuzumab treatment in breast cancer patients

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
A Banke ◽  
M Schou ◽  
J Dahl ◽  
P Frederiksen ◽  
L Videbaek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Longitudinal Strain ◽  
Troponin T ◽  
Global Longitudinal Strain ◽  
Plasma Concentrations ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Trastuzumab Treatment

Abstract Funding Acknowledgements The Danish Heart Foundation, Copenhagen (grant number: 14-R97-A5188-22839 and 15-R99-A5940). The Research Fond of the Region of Southern Denmark. Background Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. The possibility to detect signs of acute myocardial deterioration at treatment initiation is not thoroughly investigated. Accordingly, the aim of this study was to assess changes in GLS and biomarkers within the first two weeks of trastuzumab treatment. Methods In a prospective cohort study 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8% (SD ± 3.6), GLS -19.9% (SD ± 2.1), 40% hypertension) were included. Examinations including echocardiography and measurement of troponin T and NT-proBrain Natriuretic Peptide were conducted before initiation of trastuzumab, at day 3, 7 and 14 and after 3, 6 and 9 months. Results A significant deterioration in LVEF, GLS, s’, e’ septal and s’RV occurred during the 9 months study period and was proceed by significant changes in all these parameters within the first 14 days. After 14 days 12 patients (27%) had an increase in GLS ≥10 %, which was associated with significantly lower LVEF at nine month at 55.2% (SD ± 4.1) vs. 59.5% (SD ± 3.5) (p = 0.001) compared to patients with &lt;10 % early increase in GLS (Figure 1). No difference in plasma concentrations of cardiac biomarkers was observed between the two groups. Conclusion In this cohort study deteriorations in key echocardiographic parameters were detected within the first two weeks of trastuzumab treatment, and an early 10 % increase in GLS was associated with a lower LVEF at nine months. Abstract P1533 Figure 1

Simultaneous determination of disopyramide and mono-N-dealkyldisopyramide enantiomers in plasma and urine by use of a chiral cellulose-derivative column

1990 ◽  
Vol 36 (7) ◽  
pp. 1300-1304 ◽  
Author(s):  
H Echizen ◽  
K Ochiai ◽  
Y Kato ◽  
K Chiba ◽  
T Ishizaki
Keyword(s):  
Simultaneous Determination ◽  
Active Metabolite ◽  
Signal To Noise Ratio ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Cellulose Derivative ◽  
Ultraviolet Detection ◽  
Lower Detection ◽  
Relative Errors

Abstract This assay allows simultaneous determination of the enantiomers of both disopyramide and its active metabolite, mono-N-dealkyldisopyramide, in 1 mL of plasma or 0.1 mL of urine within approximately 35 min by HPLC with a chiral cellulose-derivative column and ultraviolet detection. Recoveries for the analytes and the internal standard (racemic verapamil) with an extraction from alkalinized plasma or urine into diethyl ether were greater than 90%. Intra- and interassay CVs for disopyramide enantiomers were less than 5.5% at 2.5 mg/L in plasma and less than 6.5% at 25 mg/L in urine; for mono-N-dealkyldisopyramide enantiomers they were less than 6.3% and less than 8.9%, respectively. Intra- and interassay relative errors for determining these analytes in plasma and urine at 2.5 and 25 mg/L, respectively, ranged from -5.9% to +2.5%. The calibration curves for the respective analytes were linear (r = 0.995 or greater, P less than 0.01) from 0.025 to 5.0 mg/L in plasma and from 0.5 to 10 mg/L in urine. The lower detection limits (signal-to-noise ratio of 3) for S(+)-disopyramide and the other analytes were 0.010 and 0.025 mg/L, respectively. We evaluated clinical applicability of this method by determining steady-state plasma concentrations and urinary excretions of the respective analytes in a pediatric patient being treated with racemic disopyramide.

Transcriptional up-regulation of human udp-glucuronosyltransferase (UGT) 2B17 by exemestane and its active metabolite 17-hydroexemestane in breast cancer cells

2017 ◽  
Vol 32 (1) ◽  
pp. S61
Author(s):  
Apichaya Chanawong ◽  
Dong-Gui Hu ◽  
Robyn Meech ◽  
Ross A. McKinnon ◽  
Peter I. Mackenzie
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Active Metabolite ◽  
Breast Cancer Cells ◽  
Udp Glucuronosyltransferase

Relationship Between Plasma Concentrations of Trazodone and Its Active Metabolite, m-Chlorophenylpiperazine, and Its Clinical Effect in Depressed Patients

2002 ◽  
Vol 24 (4) ◽  
pp. 563-566 ◽  
Author(s):  
Kazuo Mihara ◽  
Norio Yasui-Furukori ◽  
Tsuyoshi Kondo ◽  
Masayuki Ishida ◽  
Shingo Ono ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Clinical Effect ◽  
Plasma Concentrations ◽  
Depressed Patients

scholarly journals Plasma Concentrations of Matrilysins MMP-7 and MMP-26 as Diagnostic Biomarkers in Breast Cancer

2021 ◽  
Vol 10 (7) ◽  
pp. 1436
Author(s):  
Barbara Maria Piskór ◽  
Andrzej Przylipiak ◽  
Emilia Dąbrowska ◽  
Iwona Sidorkiewicz ◽  
Marek Niczyporuk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Levels ◽  
Proteolytic Enzymes ◽  
Plasma Concentrations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Diagnostic Utility ◽  
Study Results ◽  
Advanced Stages ◽  
Disease Study

Metalloproteinases (MMPs) are a group of proteolytic enzymes involved in the maintenance of a proper structure of extracellular matrix (ECM). Matrilysins (MMP-7 and MMP-26) are members of the MMPs group that show promise as potential breast cancer (BC) markers. The aim of the study was to evaluate plasma levels of MMP-7, MMP-26 and CA 15-3 individually and in combination and assess the diagnostic utility of studied matrilysins in patients with BC. The study group consisted of 120 patients with BC, and the control group consisted of 40 subjects with benign breast cancer and 40 healthy women. Concentrations of MMP-7 and MMP-26 were determined by enzyme-linked immunosorbent assay, and CA 15-3 by chemiluminescent microparticle immunoassay. Plasma levels of MMP-7 were significantly higher in the BC group than in the control group. Concentrations of MMP-26 and CA 15-3 were highest in stages II and IV of the disease. The highest diagnostic sensitivity was observed in stages III and IV BC for the combination of all tested markers (92.5%). The highest diagnostic specificity was noted for all tested parameters combined in the BC group (95.0%). The area under the receiver operating characteristic (ROC) curve (AUC) for the combination of markers (MMP-7+MMP-26+CA 15-3) was the largest (0.9138) in stages III and IV. Individual marker analysis showed that MMP-7 had the highest AUC (0.8894) in advanced stages of the disease. Study results indicate that MMP-7 could be used as an additional marker that would improve the diagnostic utility of CA 15-3 in early stages of BC. Therefore, the combined assessment of MMP-7 and MMP-26 with CA 15-3 might be useful in determining disease progression. Further studies are needed to evaluate whether matrilysins show promise as potential markers for improving the diagnosis of BC.

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