INDIVIDUAL 5-FLUOROURACIL DOSE INDIVIDUALIZATION IN PATIENTS WITH COLORECTAL CANCER
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2527156 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Chronotherapy demands that patients are treated at a particular time of the day in order to maximize treatment effects and minimize side effects. Chronotherapy can be personalized by taking into account the patient's circadian rhythm as measured by a repetitive sampling of gene expression over the day. As a proof of concept, the submitted model links circadian gene expression to the diurnal toxicity profile of the cancer drug irinotecan. The model is based on MODEL2109140001; it implements a transcription-translation network model of the core clock and additional genes associated with irinotecan metabolism and links this to a model of the pharmacokinetics and -dynamics (PK-PD) of irinotecan. The submitted model refines network connections of the gene regulatory network and adds a treatment-induced increase in UGT1A1 and a transient increase in the apoptosis rate in response to treatment for the PK-PD part.
2023-06-27 | MODEL2305270001 | BioModels
Project description:Tacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable inter-individual variability in pharmacokinetics (PK). Genetic and clinical factors play important roles in TAC PK. To define genetic factors associated with tacrolimus blood trough concentration, we performed a genome-wide association study of renal transplant samples from 251 Chinese renal transplant recipients. We identified 23 single nucleotide polymorphisms (SNPs) related to TAC PK variability. All 23 genome-wide significant SNPs (p<5E-8) were located on chromosome 7, including rs776746. These findings suggest that these SNPs may be associated with the unexlained TAC PK variability in renal transplant recipients and require further investigation.
2022-02-24 | GSE196772 | GEO
Project description:Pharmacokinetic/pharmacodynamic (PK/PD) studies are an essential component of pre-clinical drug discovery. Current best approaches for PK/PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PK/PD studies using transplanted human kidney organoids. We performed PK studies with GFB-887, an investigational new drug now in Phase 2 trials. Orally dosed GFB-887 to athymic rats that had undergone organoid transplantation resulted in measurable drug exposure in human transplanted organoids. Importantly, we established the efficacy of orally dosed GFB-887 in PD studies, where quantitative analysis showed significant protection of kidney filter cells in human organoids and endogenous rat host kidneys. This widely applicable approach demonstrates, for the first time, feasibility of using transplanted human organoids in PK/PD studies, empowering organoids to revolutionize drug discovery.
2022-06-14 | GSE165104 | GEO
Project description:The circadian clock controls many physiological functions in mammals, including responses to cancer therapy, by influencing the pharmacokinetics, efficacy, and toxicity of anticancer drugs. Our objective was to investigate how the timing of administration, as well as the influence of cryptochrome (Cry), a key gene in the circadian clock, impact oxaliplatin's pharmacokinetics and toxicity. Additionally, we aimed to shed light on the underlying mechanism through RNA sequencing.
2023-09-30 | GSE243491 | GEO
Project description:In this study, we evaluated the PK/PD and explored the efficacy of a PDE4 inhibitor, CC-11050 in a murine model of Mtb infection. Infected mouse lungs with or without CC-11050 treatment was also used to interrogate genome-wide transcriptional changes. Standard aerosol infection of mice with MtbCDC1551, followed by enumeration of lung bacterial load, pathology and transcriptional changes were monitored upto 112 days post infection.
2016-06-10 | GSE83188 | GEO
Project description:16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 27 samples (12 primary + 15 metastatic) from the 16 unique patients were assayed on Agilent 60K expression microarrays, and association between expression and response data were evaluated to identify potential biomarker of MK2206 response We conducted a phase 1b study of MK-2206 in combination with weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.
2016-07-31 | E-GEOD-75087 | biostudies-arrayexpress
Project description:In this study, we evaluated the PK/PD and explored the efficacy of a PDE4 inhibitor, CC-11050 in a murine model of Mtb infection. Infected mouse lungs with or without CC-11050 treatment was also used to interrogate genome-wide transcriptional changes. Standard aerosol infection of mice with MtbCDC1551, followed by enumeration of lung bacterial load, pathology and transcriptional changes were monitored upto 112 days post infection. Mice were infected with Mtb and treatment with CC11050 was started at 14 days post-infection. Uninfected mice were included as control. At 28 days post-infection, mice from all 3 groups (uninfected, Mtb-infected untreated or CC11050 treated) were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. (N=4 per group)
2016-06-10 | E-GEOD-83188 | biostudies-arrayexpress
Project description:Abstract:
Despite intensive treatments including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. A systems pharmacology approach was undertaken to investigate TMZ pharmacokinetics‐pharmacodynamics (PK‐PD) incorporating the effect of local pH, tumor spatial configuration and micro‐environment. A hybrid mathematical framework was designed coupling ordinary differential equations describing the intracellular reactions, with a spatial cellular automaton to individualize the cells. A differential drug impact on tumor and healthy cells at constant extracellular pH was computationally demonstrated as TMZ‐induced DNA damage was larger in tumor cells as compared to normal cells due to less acidic intracellular pH in cancer cells. Optimality of TMZ efficacy defined as maximum difference between damage in tumor and healthy cells was reached for extracellular pH between 6.8 and 7.5. Next, TMZ PK‐PD in a solid tumor was demonstrated to highly depend on its spatial configuration as spread cancer cells or fragmented tumors presented higher TMZ‐induced damage as compared to compact tumor spheroid. Simulations highlighted that smaller tumors were less acidic than bigger ones allowing for faster TMZ activation and their closer distance to blood capillaries allowed for better drug penetration. For model parameters corresponding to U87 glioma cells, inter‐cell variability in TMZ uptake play no role regarding the mean drug‐induced damage in the whole cell population whereas this quantity was increased by inter‐cell variability in TMZ efflux which was thus a disadvantage in terms of drug resistance. Overall, this study revealed pH as a new potential target to significantly improve TMZ antitumor efficacy.
Change the value of pH for different cases.
2019-09-30 | MODEL1909300003 | BioModels
Project description:This a model from the article:
Population-based analysis of methadone distribution and metabolism using an
age-dependent physiologically based pharmacokinetic model.
Yang F, Tong X, McCarver DG, Hines RN, Beard DA. J Pharmacokinet Pharmacodyn
2006 Aug;33(4):485-518 16758333
,
Abstract:
Limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to use
in methadone dosing recommendations in pediatric patients for either opioid
abstinence or analgesia. Considering the extreme inter-individual variability of
absorption and metabolism of methadone, population-based PK would be useful to
provide insight into the relationship between dose, blood concentrations, and
clinical effects of methadone. To address this need, an age-dependent
physiologically based pharmacokinetic (PBPK) model has been constructed to
systematically study methadone metabolism and PK. The model will facilitate the
design of cost-effective studies that will evaluate methadone PK and PD
relationships, and may be useful to guide methadone dosing in children. The PBPK
model, which includes whole-body multi-organ distribution, plasma protein
binding, metabolism, and clearance, is parameterized based on a database of
pediatric PK parameters and data collected from clinical experiments. The model
is further tailored and verified based on PK data from individual adults, then
scaled appropriately to apply to children aged 0-24 months. Based on measured
variability in CYP3A enzyme expression levels and plasma orosomucoid (ORM2)
concentrations, a Monte-Carlo-based simulation of methadone kinetics in a
pediatric population was performed. The simulation predicts extreme variability
in plasma concentrations and clearance kinetics for methadone in the pediatric
population, based on standard dosing protocols. In addition, it is shown that
when doses are designed for individuals based on prior protein expression
information, inter-individual variability in methadone kinetics may be greatly
reduced.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Yang F, Tong X, McCarver DG, Hines RN, Beard DA. (2006) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230040 | BioModels
Project description:Purpose: Patients with advanced soft-tissue sarcomas (STSs) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine—threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining (NHEJ). Experimental design: To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacological inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. Results: DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacological inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. Conclusion: DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma
2023-09-25 | GSE243758 | GEO