Cytochrome P450 2D6 status predicts breast cancer relapse in women receiving adjuvant tamoxifen (Tam)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 504-504 ◽  
Author(s):  
S. K. Knox ◽  
J. N. Ingle ◽  
V. J. Suman ◽  
J. M. Rae ◽  
D. A. Flockhart ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Plasma Concentrations ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Rank Test ◽  
Cyp2d6 Genotype ◽  
Medication History ◽  
Concurrent Administration ◽  
The North ◽  
The Impact

504 Background: CYP2D6 genetic variants and concurrent administration of potent inhibitors (Inh) of the enzyme markedly reduce the plasma concentrations of endoxifen (Jin. JNCI 2005;97:30–9). We have shown that genetic variation in CYP2D6 is associated with a higher risk of relapse in Tam treated patients (pts) (Goetz. JCO 2005;23:9312–18), but the impact of CYP2D6 inhibition on Tam clinical outcome is unknown. Methods: Using the North Central Cancer Treatment Group 89–30–52 adjuvant Tam trial (1989–1994), we evaluated the effect of co-administration of CYP2D6 Inh and CYP2D6*4 genotype on relapse in pts receiving tam alone. Patient charts were reviewed at each randomizing site to record the following known CYP2D6 Inh: fluoxetine (F), paroxetine (P), sertraline (S), cimetidine (C), amiodarone (A), doxepin (D), ticlopidine (T) and haloperidol (H). Poor metabolizers (PM) were defined as pts who were CYP2D6 *4/*4 and/or known to receive a CYP2D6 Inh. Intermediate metabolizers (IM) were defined as WT/*4 without CYP2D6 Inh, and extensive metabolizers (EM) as WT/WT without CYP2D6 Inh. The association between CYP2D6 status and Tam clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors. Results: CYP2D6*4 genotype was obtained in 190 of 256 eligible pts, with a CYP2D6*4/*4 genotype frequency of 6.8% as described previously (Goetz JCO 2005). Medication history was available in 171/256 eligible pts and in 143/190 pts with CYP2D6 genotype. Eleven of 173 patients were concomitantly administered these CYP2D6 Inh: F(2), P(2), S(2), H(1), C(4), and D(1). The median duration of use was 2.5 yrs. Twenty-four pts met criteria for PM [13 by *4/*4 genotype and 11 by CYP2D6 Inh (7 WT/WT, 1 WT/*4, and 3 unknown genotype)], 21 for IM, and 102 for EM. Compared with either IM or EM, PMs had significantly worse time to recurrence and disease free survival in both the univariate (HR 2.5, p=0.02; and 2.2, p=0.01) and multivariate (HR 2.7, p=0.01; and HR 2.2 p=.02) analyses utilizing tumor size, nodal status, and tumor grade. Conclusion: Our data indicate that CYP2D6 status can be used to identify pts who should receive tam therapy and tam treated pts should not be co-administered potent CYP2D6 inhibitors. No significant financial relationships to disclose.

scholarly journals Clinicopathological and Prognostic Value of CD24 Expression in Breast Cancer: A Meta-Analysis

2017 ◽  
Vol 32 (2) ◽  
pp. 182-189
Author(s):  
Gao Liu ◽  
Guo-Xing Liu ◽  
Yu Fang ◽  
Zhen-Yu Cao ◽  
Hui-Hui Du ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Pooled Analysis ◽  
Tnm Stage ◽  
Her2 Status ◽  
Relative Risk Ratio ◽  
The Impact

Background A number of studies have been conducted to explore the relationship between CD24 expression and the prognosis of breast cancer; however, the results remain inconsistent. Therefore, we performed this meta-analysis to clarify the impact of CD24 expression on clinicopathological features and prognosis of breast cancer. Methods A comprehensive literature search for relevant studies was performed, and statistical analysis was conducted using Stata software. Results Twenty studies, including 5,179 cases, were included in this meta-analysis. The pooled analysis indicated that CD24 expression was associated with lymph node invasion (odds ratio [OR] = 0.68, for negative vs. positive, 95% confidence interval [95% CI], 0.53-0.87, p = 0.002) and TNM stage (OR = 0.63, for I + II vs. III + IV, 95% CI, 0.49-0.81, p<0.001). The prognosis analysis also suggested CD24 overexpression indicated a poorer 5-year overall survival (OS) rate (relative risk ratio [RR] = 0.93, 95% CI, 0.86-0.99, p = 0.03) and 5-year disease-free survival (DFS) rate (RR = 0.90, 95% CI, 0.83-0.98, p = 0.02). However, CD24 expression had no correlation with tumor size, tumor grade, distance metastasis, estrogen receptor (ER) status, progesterone receptor (PR) status, or HER2 status. Conclusions Our results suggest that higher CD24 expression is significantly associated with lower OS rate, lower DFS rate and some clinicopathological factors such as lymph node invasion and TNM stage. This meta-analysis suggested that CD24 is an efficient prognostic factor in breast cancer.

Sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer: Experience of a Brazilian oncological center.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12105-e12105
Author(s):  
Daniel D’Almeida Preto ◽  
André Octavio Nicolau Sanches ◽  
Alison Wagner Azevedo Barroso ◽  
Alessandra Caroline Moretto Carbinatto ◽  
Ana Lima Veneziani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Cancer Center ◽  
Survival Times ◽  
Number Of Patients ◽  
The Impact

e12105 Background: The best sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer is still unknown. The aims of this study were to assess the impact of the sequence order in the pathological complete response (pCR) rate, and in the disease free survival (DFS) and overall survival (OS). Methods: We retrospectively reviewed 235 HER2-negative breast cancer women treated with neoadjuvant chemotherapy from 2003 to 2011 at our cancer center. The patients were pooled in two groups: anthracycline-based followed by taxanes (AC-T) and the reverse sequence (T-AC). The chi-square test was performed to verify the homogeneity between the groups and to compare pCR rate among the treatment groups. Cumulative survival probabilities were calculated using the Kaplan-Meier method. Differences between survivals were tested using the log-rank test. Results: The AC-T (n = 161) and T-AC (n = 74) groups were balanced for age, staging, receptor profile and histologic grade. The follow-up was at least five years for each patient. The median age was 50.1 years. Most patients (97%) had stage III tumors and 72 (30%) had triple negative disease. pCR rate was higher in triple negative compared with luminal cases (16.3 vs. 7.3%; p = 0.049). Treatment sequence did not influence the occurrence of pCR (10.5 vs. 8.5%; p = 0.8) or median survival times (DFS: 87.9 vs. 64.1, p = 0.85; OS: 91.1 vs. 71.6 months, p = 0.15), in the AC-T and T-AC groups, respectively. Conclusions: The sequence of neoadjuvant taxane-anthracycline-based chemotherapy regimen in daily practice did not show difference in the evaluated clinical outcomes. The retrospective design and the low number of patients may limit the power of the study to detect statistically significant differences. Phase III trials should be stimulated in this context. [Table: see text]

Combined treatment of patients with bone metastases from various cancers with nivolumab plus denosumab: A retrospective study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14153-e14153
Author(s):  
Yukinori Ozaki ◽  
Yuji Miura ◽  
Taro Yamanaka ◽  
Kohji Takemura ◽  
Rika Kizawa ◽  
...  
Keyword(s):  
Survival Rate ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Rank Test ◽  
Concurrent Administration ◽  
Free Survival ◽  
Primary Disease ◽  
The Impact

e14153 Background: Monoclonal antibodies against the programmed cell death protein-1 (PD-1), e.g., nivolumab, have been shown to exhibit antitumor immunity and improve survival in patients with various cancers. Recently, it was reported that bone metastases are unlikely to respond to immunotherapy, while other reports have suggested that synergistic antitumor effect can be obtained by administration of denosumab in combination with PD-1 blockade using nivolumab. However, there are still very limited data on the efficacy and effects on the prognosis of nivolumab administered in combination with denosumab in patients with bone metastases. Methods: We reviewed the medical records and pharmacy database of patients who had received nivolumab plus denosumab treatment from April 2011 to March 2018 at our institution, in order to analyze the prognosis of patients with bone metastases from various cancers. The primary objective was to compare the progression-free survival between patients with and without bone metastases. The impact of combined nivolumab plus denosumab therapy was evaluated as an exploratory endpoint. Results: We extracted 201 patients who had received denosumab for bone metastasis and 45 patents who had received immune checkpoint inhibitor. We analyzed the data of 39 patients who had received nivolumab treatment; of these 39 patients, 10 had additionally also received denosumab for the treatment of bone metastases. The median age of the patients was 65 years (range 41-87); the primary disease was renal cell carcinoma in 17 patients, gastric cancer in 9 patients, melanoma in 6 patients, non-small cell lung cancer in 4 patients, and head and neck cancer in 3 patients. The median progression-free survival following treatment with nivolumab was 2.1 months in the group with bone metastases and 3.5 months in the group without bone metastases (log-rank test; p = 0.0779); the 6-month progression-free survival rate was 26.7% (95% CI: 21.6-69.2) in the patients with bone metastases and 39.3% (95% CI: 10.4-53.3) in those without bone metastases. Concurrent administration of denosumab, age, and the primary disease had no influence on the progression-free survival rate. Conclusions: This retrospective analysis revealed a trend towards lower immune responses in patients with bone metastases, even when nivolumab is administered in combination with denosumab. Immunotherapy for bone metastasis needs to be further explored.

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

2007 ◽  
Vol 25 (25) ◽  
pp. 3837-3845 ◽  
Author(s):  
Hyeong-Seok Lim ◽  
Han Ju Lee ◽  
Keun Seok Lee ◽  
Eun Sook Lee ◽  
In-Jin Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Steady State ◽  
Clinical Outcome ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Pregnane X Receptor ◽  
Cyp2d6 Genotype ◽  
Breast Cancer Patients ◽  
State Plasma

Purpose The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. Patients and Methods Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. Results Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) Conclusion CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

Birth Order Does Not Affect Outcome in HLA-Identical Sibling Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5003-5003
Author(s):  
Edward Copelan ◽  
Ronald Sobecks ◽  
Robert Dean ◽  
Lisa Rybicki ◽  
Stacey Brown ◽  
...  
Keyword(s):  
Stem Cell ◽  
Birth Order ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Rank Test ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Male Donor ◽  
The Impact

Abstract Fetomaternal and transmaternal sibling microchimerism might result in tolerance of hematopoietic stem-cell donors to recipients who were born before them. A single clinical study comparing first-born recipients and first-born donors provided evidence that birth order can have a significant impact on survival and on the incidence of acute graft-versus-host disease (GVHD) and relapse in HLA-identical sibling transplantation. In order to determine whether birth order might exert a consistent, biologically important effect, we compared survival and the incidence of acute GVHD, chronic GVHD, and relapse in recipients of HLA-identical transplants from sibling donors older than themselves to recipients with younger sibling donors. From 11/84 through 11/06, 410 first HLA-identical sibling transplants were performed. Patients were categorized by whether the sibling donor was older (n=187) or younger (n=223) than the recipient. As expected, the two groups differed with respect to patient age (P<0.001). The groups were similar with respect to gender, diagnosis, interval from diagnosis to transplant, extent of prior treatment, preparative regimen, stem-cell source, donor to patient gender, and CD34+ cell dose. Outcomes were estimated using the Kaplan-Meier Method and compared between the birth order groups using the log rank test. The incidence of acute GVHD, ≥ grade II acute GVHD, chronic GVHD, extensive chronic GVHD, relapse, survival, and disease-free survival were similar (0.39≤P≤0.85) between the two groups. The incidence of acute GVHD and survival in the two groups is shown below: Figure Figure Figure Figure After adjustment for differences between the two groups, multivariable assessment of sibling birth order was not prognostic for survival (P=.32). Only older (P=0.029) and male donor/female recipient (P=.017) were independent prognostic adverse factors. In this large study of the HLA-identical sibling transplantation, no impact of birth order on the incidence of GVHD, relapse incidence, or survival was detected. Although (because of different methodologies) not directly contradictory to a previous study of birth order, the present results suggest that further study of the impact of birth order on outcome of HLA-identical sibling transplantation is needed. Suggestions that birth order be integrated into donor-selection algorithms or that matched unrelated donors might be preferred to high-risk HLA identical siblings are premature.

Microsatellite instability status as a predictive marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 493-493 ◽  
Author(s):  
A. Zaanan ◽  
J. Flejou ◽  
J. Emile ◽  
P. Validire ◽  
C. Louvet ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Chemotherapy ◽  
Clinical Outcome ◽  
Microsatellite Instability ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Rank Test ◽  
Free Survival ◽  
Stage Iii Colon Cancer

493 Background: The addition of oxaliplatin to 5-fluorouracil (5-FU; FOLFOX regimen) was demonstrated to improve the adjuvant treatment of stage III colon cancer. For patients with microsatellite instability (MSI) tumors, several studies suggested a lack of benefit from 5-FU adjuvant chemotherapy but very little data are available regarding FOLFOX adjuvant therapy. The aim of this study was to further assess the value of MSI status as a marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer. Methods: This multicentric retrospective study included 223 unselected patients with stage III colon cancer treated by FOLFOX adjuvant chemotherapy between 2003 and 2007. MSI status was determined by immunohistochemistry as the absence of MLH1, MSH2 or MSH6 expression. Disease-free survival (DFS) and relapse-free survival (RFS) were analyzed according to the MSI status using Kaplan Meier method and compared by log-rank test. Results: Twenty three tumors (10.3%) were MSI. The rate of 3-year DFS was 88.6% and 76.6% for MSI and MSS groups, respectively (HR=0.64; 95% CI, 0.25 to 1.60; P=0.34). The rate of 3-year RFS was 88.6% and 76.7% for MSI and MSS groups, respectively (HR=0.52; 95% CI, 0.20 to 1.30; P=0.18). Conclusions: A trend toward longer survival was observed for patients with MSI tumors compared with those with MSS tumors but the differences in survival were not significant. Interestingly, DFS at 3-years of patients with stage III MSI tumors treated by FOLFOX was higher in our series (88.6%) than in the largest study published for patients treated by 5-FU-based adjuvant chemotherapy (around 67.5%) or surgery alone (around 62.5%) (Sargent et al, JCO 2010). These observations suggest that adding oxaliplatin to 5-FU re-establishes a benefit of adjuvant treatment in the stage III MSI population. These results should be confirmed by analyzing materials of previously completed trials comparing FOLFOX to 5-FU such as the MOSAIC study. [Table: see text]

The impact of renal cell carcinoma histopathological subtype on disease prognosis: A Canadian multi-institutional analysis.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 480-480
Author(s):  
Jennifer Bjazevic ◽  
Jasmir G. Nayak ◽  
Premal Patel ◽  
Anil Kapoor ◽  
Simon Tanguay ◽  
...  
Keyword(s):  
Clear Cell ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Type I ◽  
Histological Subtype ◽  
Free Survival ◽  
Papillary Type ◽  
The Impact ◽  
Disease Free

480 Background: Renal cell carcinoma (RCC) is divided into several histopathological subtypes, each with significantly different clinical features. However, current data regarding the prognostic value of histological subtype is limited and conflicted. We examined the impact of RCC histology on disease prognosis in a large, multi-institutional Canadian analysis. Methods: The Canadian Kidney Cancer Information System (CKCis), a prospective database from 14 Canadian institutions, was utilized for the study. 1284 patients with non-metastatic RCC, who underwent surgical intervention with curative intent, were included in the study. Patients were stratified according to their primary histology and the Chi-squared test was used to determine associations between histopathology and clinical features. The impact of histology of disease-free survival (DFS) was determined with a multivariate analysis adjusted for age, gender, tumor size, tumor grade, and pathological stage. Results: Clear cell RCC was the most prevalent histological subtype found in 80.5% of patients. Histopathology was significantly associated with patient age, tumor grade, and pathological stage. Advanced stage disease (>T3) was associated with clear cell and papillary type II RCC (p<0.05). 90.7%, 86.7%, 78.5%, and 78.8% of patients with chromophobe, papillary type I, papillary type II, and clear cell RCC respectively, were free of disease after a median follow-up of 1.2 years. On multivariate analysis, histological subtype was a significant predictor of disease-free survival (DFS). When compared to clear cell histology, chromophobe RCC had a significantly higher DFS (HR=0.38, 95% CI 0.15-0.95, p<0.05), and papillary type I RCC had a trend towards a lower rate of disease progression (HR=0.31, 95% CI 0.08-1.28, p=0.05). Conclusions: This study demonstrates that histological subtype impacts disease progression. Histological subtype was independently associated with DFS in surgically treated RCC, specifically chromophobe RCC was shown to have the highest DFS. This may be used to help individualize patient treatment and follow-up based on primary tumor histology.

Effect of Pancreatic Fistula on Recurrence and Long-Term Prognosis of Periampullary Adenocarcinomas after Pancreaticoduodenectomy

2016 ◽  
Vol 82 (12) ◽  
pp. 1187-1195 ◽  
Author(s):  
Pablo E. Serrano ◽  
Dowan Kim ◽  
Peter T. Kim ◽  
Paul D. Greig ◽  
Carol-Anne Moulton ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Pancreatic Fistula ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Free Survival ◽  
Resection Margin Status ◽  
Long Term Prognosis ◽  
The Impact

Pancreatic fistula (PF) is common after pancreaticoduodenectomy (PD). Its effect on recurrence and survival is not known. Retrospective study of patients undergoing PD for periampullary adenocarcinomas (2000–2012). Standard statistical analyses were performed to determine the impact of PF on disease-free survival (DFS) and overall survival (OS). There were 634 PDs (pancreatic adenocarcinoma: 347, other periampullary adenocarcinomas: 287). Any-grade PF developed in 81/634 (13%). Perioperative mortality rate was 1.7 per cent (11/634), higher in patients with PF (10 vs 0.5%, P < 0.001). In multivariable analysis, PF significantly reduced DFS in pancreatic [hazard ratio (HR) = 1.6, 95% confidence-interval (CI): 1.1–2.6, P = 0.043] but not in other periampullary adenocarcinomas [HR = 1.3 (95% CI: 0.8–2.2), P = 0.45]. Positive lymph nodes, margins, and high-grade histology were associated with decreased DFS and OS. Adjuvant therapy was associated with improved OS in pancreatic [HR = 0.7 (95% CI: 0.5–0.9), P = 0.02] but not in other periampullary adenocarcinomas [HR = 1.14 (95% CI: 0.8–1.7), P = 0.49]. PF did not alter OS in either group. After PD, PF is associated with decreased DFS in pancreatic but not in other periampullary adenocarcinomas. This decrease DFS did not alter OS. Tumor grade, lymph nodes, and resection margin status are associated with DFS and OS.

Clinical Outcome of the ACCORD 12/0405 PRODIGE 2 Randomized Trial in Rectal Cancer

2012 ◽  
Vol 30 (36) ◽  
pp. 4558-4565 ◽  
Author(s):  
Jean-Pierre Gérard ◽  
David Azria ◽  
Sophie Gourgou-Bourgade ◽  
Isabelle Martel-Lafay ◽  
Christophe Hennequin ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Outcome ◽  
Social Life ◽  
Disease Free Survival ◽  
Clinical Results ◽  
Preoperative Chemoradiotherapy ◽  
Significant Prognostic Factor ◽  
Concurrent Administration ◽  
Operative Specimen ◽  
Significant Difference

Purpose The ACCORD 12 trial investigated the value of two different preoperative chemoradiotherapy (CT-RT) regimens in T3-4 Nx M0 resectable rectal cancer. Clinical results are reported after follow-up of 3 years. Patients and Methods Between November 2005 and July 2008, a total of 598 patients were randomly assigned to preoperative CT-RT with CAP45 (45-Gy RT for 5 weeks with concurrent capecitabine) or CAPOX50 (50-Gy RT for 5 weeks with concurrent capecitabine and oxaliplatin). Total mesorectal excision was planned 6 weeks after CT-RT. The primary end point was sterilization of the operative specimen, which was achieved in 13.9% versus 19.2% of patients, respectively (P = .09). Clinical results were analyzed for all randomly assigned patients according to the intention-to-treat principle. Results At 3 years, there was no significant difference between CAP45 and CAPOX50 (cumulative incidence of local recurrence, 6.1% v 4.4%; overall survival, 87.6% v 88.3%; disease-free survival, 67.9% v 72.7%). Grade 3 to 4 toxicity was reported in four patients in the CAP45 group and in two patients in the CAPOX50 group. Bowel continence, erectile dysfunction, and social life disturbance were not different between groups. In multivariate analysis, the sterilization rate (Dworak score) of the operative specimen was the main significant prognostic factor (hazard ratio, 0.32; 95% CI, 0.21 to 0.50). Conclusion At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended.

scholarly journals Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Johannes Matthaei ◽  
Jürgen Brockmöller ◽  
Werner Steimer ◽  
Konstanze Pischa ◽  
Stefan Leucht ◽  
...  
Keyword(s):  
Genetic Polymorphism ◽  
Depressive Disorder ◽  
Healthy Volunteers ◽  
Organic Cation ◽  
Plasma Concentrations ◽  
Organic Cation Transporter ◽  
Independent Study ◽  
Interindividual Variation ◽  
Cyp2d6 Genotype ◽  
The Impact

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

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