Explaining Interindividual Variability of Docetaxel Pharmacokinetics and Pharmacodynamics in Asians Through Phenotyping and Genotyping Strategies

2002 ◽  
Vol 20 (17) ◽  
pp. 3683-3690 ◽  
Author(s):  
Boon-Cher Goh ◽  
Soo-Chin Lee ◽  
Ling-Zhi Wang ◽  
Lu Fan ◽  
Jia-Yi Guo ◽  
...  
Keyword(s):  
Interindividual Variability ◽  
Performance Status ◽  
Regulatory Region ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Pharmacokinetic Data ◽  
Data Sets ◽  
Pharmacokinetics And Pharmacodynamics ◽  
C3435t Polymorphism ◽  
And Performance

PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1. RESULTS: Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5′ regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients. CONCLUSION: Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory irinotecan-naïve advanced colorectal cancer (CRC): dose-finding, pharmacokinetics, safety and efficacy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13520-13520
Author(s):  
T. Hickish ◽  
I. Chau ◽  
A. Massey ◽  
L. Higgins ◽  
R. Osborne ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Performance Status ◽  
Tumour Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Dose Schedule ◽  
Dose Finding ◽  
Pharmacokinetic Data ◽  
And Performance ◽  
Neo Adjuvant Chemotherapy

13520 Background: Gefitinib (IRESSA) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown supra-additive activity in human CRC xenografts when combined with irinotecan. We have previously established that the recommended dose level (RDL) to be irinotecan 225mg/m2 q3 weeks and gefitinib 250mg daily (Chau et al ASCO 2004). The dose limiting toxicities were neutropenia and diarrhoea. The continuation phase of this study aimed to evaluate the efficacy and safety of this combination. Patients and Methods: Between Jun 2002 and Feb 2005, patients (pts) with advanced CRC progressing on or within 12 weeks of fluoropyrimidines-based chemotherapy, irinotecan-naïve and performance status ≤2 were recruited. Thirty-nine pts were treated with irinotecan and gefitinib in total with 27 treated at the RDL. Results: Median age was 61 years (range: 31–79) and 13 (33.3%) pts were females. All pts were Caucasians (94.9%) and non-oriental Asians (5.1%). Thirteen (33.3%) pts had received (neo)adjuvant chemotherapy and 16 (41.0%) pts had prior oxaliplatin-based chemotherapy for metastatic disease. Grades 3–4 toxicities were anaemia 2.6%, neutropenia 15.4%, febrile neutropenia 10.3%, diarrhoea 35.9%, nausea 2.6%, vomiting 5.1%, lethargy 15.4% and skin rash 7.7%. For the pts treated at RDL, the objective tumour response rate was 11.1% (3 partial responses [PRs]; 95% confidence interval [CI]: 2.4–29.2%) and the disease control rate was 40.7% (3PRs, 8 stable diseases lasting for ≥12 weeks). The median time to progression was 4.2 months and median survival was 9.3 months. Six-month progression free survival was 22.2% (95% CI: 6.5–37.9%) and 6-month overall survival was 73.4% (95% CI: 56.5–90.3%). Preliminary pharmacokinetic data suggested that the addition of irinotecan to gefitinib resulted in an average of 14–33% increase in exposure to gefitinib (p<0.05). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable. Gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC may be contributory to the modest activity of irinotecan and gefitinib combination. [Table: see text]

scholarly journals Leukocyte Telomere Length and Serum Levels of High-Molecular-Weight Adiponectin and Dehydroepiandrosterone-Sulfate Could Reflect Distinct Aspects of Longevity in Japanese Centenarians

2017 ◽  
Vol 3 ◽  
pp. 233372141769667
Author(s):  
Yuji Aoki ◽  
Masato Aoki ◽  
Kazuya Yamada
Keyword(s):  
Molecular Weight ◽  
Telomere Length ◽  
High Molecular Weight ◽  
Performance Status ◽  
Serum Levels ◽  
Dehydroepiandrosterone Sulfate ◽  
Leukocyte Telomere Length ◽  
Protection Assay ◽  
High Molecular Weight Adiponectin ◽  
And Performance

Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S) were assessed in association with nutrition and performance status (PS) in Japanese centenarians. Twenty-three centenarians (five men, 18 women) were classified according to their PS 1 (nearly fully ambulatory, n = 2), 2 (in bed less than 50% of daytime, n = 10), 3 (in bed greater than 50%, n = 6), and 4 (completely bedridden, n = 5). Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI), albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin ( r = −.694, p < .01), between telomere length and BMI ( r = .522, p < .05), between adiponectin and BMI ( r = −.574, p < .01), and between DHEA-S and albumin ( r = .530, p < .01). When excluding two cancer-bearing centenarians with short telomere, telomere length significantly correlated with PS ( r = −.632, p < .01). It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.

L-carnitine supplementation improves fatigue, mood and sleep in cancer patients with fatigue and carnitine deficiency

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8588-8588 ◽  
Author(s):  
R. A. Cruciani ◽  
E. Dvorkin ◽  
P. Homel ◽  
B. Culliney ◽  
S. Malamud ◽  
...  
Keyword(s):  
Performance Status ◽  
Serum Levels ◽  
Maximum Tolerated Dose ◽  
Carnitine Deficiency ◽  
Free Carnitine ◽  
Dependent Manner ◽  
Carnitine Supplementation ◽  
Karnofsky Score ◽  
Full Dataset ◽  
And Performance

8588 Background: Carnitine is a natural aminoacid derivative that plays a crucial role in cellular energy metabolism. To determine the dose and tolerability we conducted a phase II study with increasing doses of L-carnitine supplementation. In a preliminary analysis, we reported that L-carnitine could improve fatigue, mood and sleep. (Cruciani et al., 2004). Analysis of the full dataset has confirmed and extended these findings. Methods: Patients had active cancer, fatigue and a Karnofsky ≥50. Carnitine deficiency was defined as free carnitine <35 μm]/L for males and <25 for females (normal range 35–67 and 25–55 respectively), or a ratio of acyl/free carnitine >0.4. We utilized a standard maximum tolerated dose (MTD) design, with 3 patients assigned to each successive dose group, starting at 250 mg/day and increasing in each group by 500 mg/day to a maximum dose target of 3000 mg/day. Fatigue (measured by the BFI), depressed mood (CES-D), quality of sleep (ESS), and performance status (Karnofsky), as well as carnitine serum levels were assessed at baseline and after one week of L-carnitine supplementation. Results: Seven groups of three patients each received L-carnitine supplementation for a week with 250, 750, 1,250, 1,750, 2,250, 2,750 or 3,000 mg/day. Of the 27 patients accrued 21 completed the study. Of these, 17 (mean (SD) age = 63.0 (18), females=8) showed an increase in serum L-carnitine levels. The median (min, max) total carnitine increased from 31 (21, 68) to 51 (29, 111) (p < 0.001) and the free carnitine increased from 25.0 (17, 48) to 39 (25, 82) (p < 0.001). The median (min, max) BFI score at baseline was 63 (36, 81) versus 39 (8, 82) after one week (p<0.001). There was also a significant dose response for BFI (r = -0.61, p = 0.01). Median (min, max) CES-D at baseline was 31. (4, 48) and 18.0 (0, 40) after one-week (p = 0.001). Median (min, max) ESS at baseline was 13.7 (2, 22) and 10.3 (1, 18) after one week (p=0.003). Median Karnofsky score did not change (pre and post = 70). Side effects were not observed in any of the groups. Conclusions: This study suggests that L-carnitine is safe up to 3,000 mg/day. Supplementation was associated with improvements in fatigue and depression scores. Fatigue improved in a dose dependent manner. [Table: see text]

scholarly journals Software Benchmark—Classification Tree Algorithms for Cell Atlases Annotation Using Single-Cell RNA-Sequencing Data

2021 ◽  
Vol 12 (2) ◽  
pp. 317-334
Author(s):  
Omar Alaqeeli ◽  
Li Xing ◽  
Xuekui Zhang
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Classification Tree ◽  
Area Under The Curve ◽  
Data Sets ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing ◽  
Tree Algorithms ◽  
R Packages

Classification tree is a widely used machine learning method. It has multiple implementations as R packages; rpart, ctree, evtree, tree and C5.0. The details of these implementations are not the same, and hence their performances differ from one application to another. We are interested in their performance in the classification of cells using the single-cell RNA-Sequencing data. In this paper, we conducted a benchmark study using 22 Single-Cell RNA-sequencing data sets. Using cross-validation, we compare packages’ prediction performances based on their Precision, Recall, F1-score, Area Under the Curve (AUC). We also compared the Complexity and Run-time of these R packages. Our study shows that rpart and evtree have the best Precision; evtree is the best in Recall, F1-score and AUC; C5.0 prefers more complex trees; tree is consistently much faster than others, although its complexity is often higher than others.

scholarly journals Prognostic value of blood-based fibrosis biomarkers in patients with metastatic colorectal cancer receiving chemotherapy and bevacizumab

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Neel I. Nissen ◽  
Stephanie Kehlet ◽  
Mogens K. Boisen ◽  
Maria Liljefors ◽  
Christina Jensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Collagen Type ◽  
Performance Status ◽  
Drug Uptake ◽  
Collagen Type Iii ◽  
Serum Samples ◽  
Type Iii ◽  
Poor Treatment ◽  
And Performance

AbstractA desmoplastic colorectal cancer stroma, characterized by excess turnover of the cancer-associated fibroblast derived collagens type III and VI, can lead to reduced drug-uptake and poor treatment response. We investigated the association between biomarkers of collagen type III and VI and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Serum samples were collected from 252 patients with mCRC prior to treatment with bevacizumab and chemotherapy. Serum concentrations of biomarkers reflecting formation of collagen type III (PRO-C3) and VI (PRO-C6) and degradation of collagen type VI (C6M and C6Mα3) were determined by ELISA. The biomarkers were evaluated for associations with OS, individually, combined, and after adjusting for carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH) and performance status (PS). High baseline levels (> median) of each collagen biomarker were significantly associated with shorter OS (PRO-C3: HR = 2.0, 95%CI = 1.54–2.63; PRO-C6: HR = 1.6, 95%CI = 1.24–2.11; C6M: HR = 1.4, 95%CI = 1.05–1.78; C6Mα3: HR = 1.6, 95%CI = 1.16–2.07). PRO-C3 and PRO-C6 remained significant after adjustment for CEA, LDH and PS. Weak correlations were seen between the collagen biomarkers (r = 0.03–0.59) and combining all improved prognostic capacity (HR = 3.6, 95%CI = 2.30–5.76). Collagen biomarkers were predictive of shorter OS in patients with mCRC. This supports that collagen- and CAF biology is important in CRC.

Pharmacokinetics and Pharmacodynamics of Antistaphylococcal Antibiotics in Continuous Ambulatory Peritoneal Dialysis Patients

1993 ◽  
Vol 13 (2_suppl) ◽  
pp. 367-371 ◽  
Author(s):  
Erich Keller
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Inhibitory Concentration ◽  
Pharmacokinetic Data ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Antistaphylococcal Activity ◽  
Cure Rates ◽  
Vitro Data ◽  
In Vitro Data

Staphylococci are the leading pathogens In continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Vancomycin appears to be an outstanding antistaphylococcal drug because resistance to It Is nearly absent. The pharmacokinetics of vancomycin and clinical cure rates of peritonitis with different dosing guidelines have been studied extensively. Different dosing guidelines with IP or IV loading doses followed or not followed by IP maintenance doses are used successfully, despite the fact that some of the dosing schemes produce apparently suboptimal drug levels referring to In vitro data like the MIC value (minimum Inhibitory concentration). Alternatively, amlnoglycosldes, cephalosporlns, Isoxazolyl penicillins, and broad-spectrum penicillins combined with betalactamase Inhibitors may be used for the treatment of gram-positive peritonitis. For the above panicillins pharmacokinetic data are scarce, and clinical experience is limited. Rifampin has excellent Intracellular antistaphylococcal activity and should be used In combination with other antibiotics. Although pharmacokinetic data are lacking, rifampin dosages do not require adaptation to renal function or replacement therapy.

Alterations of serum levels of plasminogen, TNF-α, and IDO in granulomatosis with polyangiitis patients

Vascular ◽  
2021 ◽  
pp. 170853812098630
Author(s):  
Dobroslav Kyurkchiev ◽  
Tsvetelina Yoneva ◽  
Adelina Yordanova ◽  
Ekaterina Kurteva ◽  
Georgi Vasilev ◽  
...  
Keyword(s):  
Granulomatosis With Polyangiitis ◽  
Renal Involvement ◽  
Clinical Manifestations ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Necrosis Factor Alpha ◽  
Cross Sectional ◽  
Spearman's Rho ◽  
Tnf Α ◽  
Spearman’S Rho

Background Granulomatosis with polyangiitis (GPA) is a representative of vasculitides associated with anti-neutrophil cytoplasmic autoantibodies. “Classical” antibodies directed against proteinase 3 are involved in the pathogenesis and are part of the GPA diagnosis at the same time. Along with them, however, antibodies against Lysosomal-Associated Membrane Protein-2 (LAMP-2) and antibodies directed against plasminogen have been described in GPA. Objectives and methodology: We performed a cross-sectional study enrolling 34 patients diagnosed with GPA. Our study was aimed at looking for correlations between serum levels of LAMP-2 and plasminogen and the clinical manifestations of the GPA. Furthermore, we examined serum levels of tumor necrosis factor-alpha (TNF-α) and its associated indoleamine-pyrrole 2,3-dioxygenase (IDO), as well as we looked for a correlation between these cytokines and the clinical manifestations of GPA. Results The results showed that in GPA, serum plasminogen levels were negatively associated with renal involvement (receiver operating characteristic (ROC) area under the curve (AUC) of 0.78) (95% CI 0.53–0.91), p = 0.035, and the extent of proteinuria, Spearman’s Rho = –0.4, p = 0.015. Increased levels of TNF-α and IDO correlated with disease activity, Spearman’s Rho =0.62, p = 0.001 and Spearman’s Rho = 0.4, p = 0.022, respectively, whereas only TNF-α was increased in severe forms of GPA with lung involvement (ROC AUC of 0.8) (95% CI 0.66–0.94), p = 0.005. Conclusions In this study, we demonstrate the alteration of soluble factors, which play an important role in the pathogenesis of GPA and their relationship with the clinical manifestations of the disease. Our main results confirm the associations of increased secretory TNF-α and some clinical manifestations, and we describe for the first time decreased serum plasminogen levels and their association with renal involvement.

scholarly journals Discovery and Evaluation of Protein Biomarkers as a Signature of Wellness in Late-Stage Cancer Patients in Early Phase Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2443
Author(s):  
Bethany Geary ◽  
Erin Peat ◽  
Sarah Dransfield ◽  
Natalie Cook ◽  
Fiona Thistlethwaite ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Early Phase ◽  
Characteristic Curve ◽  
Performance Status ◽  
Area Under The Curve ◽  
Protein Biomarkers ◽  
Late Stage Cancer ◽  
Early Phase Clinical Trials

TARGET (tumour characterisation to guide experimental targeted therapy) is a cancer precision medicine programme focused on molecular characterisation of patients entering early phase clinical trials. Performance status (PS) measures a patient’s ability to perform a variety of activities. However, the quality of present algorithms to assess PS is limited and based on qualitative clinician assessment. Plasma samples from patients enrolled into TARGET were analysed using the mass spectrometry (MS) technique: sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. SWATH-MS was used on a discovery cohort of 55 patients to differentiate patients into either a good or poor prognosis by creation of a Wellness Score (WS) that showed stronger prediction of overall survival (p = 0.000551) compared to PS (p = 0.001). WS was then tested against a validation cohort of 77 patients showing significant (p = 0.000451) prediction of overall survival. WS in both sets had receiver operating characteristic curve area under the curve (AUC) values of 0.76 (p = 0.002) and 0.67 (p = 0.011): AUC of PS was 0.70 (p = 0.117) and 0.55 (p = 0.548). These signatures can now be evaluated further in larger patient populations to assess their utility in a clinical setting.

scholarly journals An Electronic Component Recognition Algorithm Based on Deep Learning with a Faster SqueezeNet

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yuanyuan Xu ◽  
Genke Yang ◽  
Jiliang Luo ◽  
Jianan He
Keyword(s):  
Deep Learning ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Principal Component ◽  
Recognition Algorithm ◽  
Electronic Component ◽  
Support Vector ◽  
Learning Networks ◽  
Component Recognition ◽  
And Performance

Electronic component recognition plays an important role in industrial production, electronic manufacturing, and testing. In order to address the problem of the low recognition recall and accuracy of traditional image recognition technologies (such as principal component analysis (PCA) and support vector machine (SVM)), this paper selects multiple deep learning networks for testing and optimizes the SqueezeNet network. The paper then presents an electronic component recognition algorithm based on the Faster SqueezeNet network. This structure can reduce the size of network parameters and computational complexity without deteriorating the performance of the network. The results show that the proposed algorithm performs well, where the Receiver Operating Characteristic Curve (ROC) and Area Under the Curve (AUC), capacitor and inductor, reach 1.0. When the FPR is less than or equal 10 − 6   level, the TPR is greater than or equal to 0.99; its reasoning time is about 2.67 ms, achieving the industrial application level in terms of time consumption and performance.

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