Study on the effects of an OCT2/MATE1 substrate (metformin) and inhibitor (cimetidine) on the exposure of trifluridine/tipiracil (Lonsurf) in patients with metastatic colorectal cancer (mCRC).
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer With An Indication For Lonsurf Treatment
PROVIDER: 2442600 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Primary objectives: 1. To determine the possible drug interaction between Lonsurf and metformin on Lonsurf plasma pharmacokinetics (AUC) in patients with metastatic colorectal cancer.2. To determine the possible interaction between Lonsurf and cimetidine on Lonsurf plasma pharmacokinetics (AUC) in patients with metastatic colorectal cancer. of concomitant administration of Lonsurf with metformin and cimetidine on Lonsurf and metformin exposure.
Primary endpoints: To determine the influence of concomitant administration of Lonsurf with metformin and cimetidine on Lonsurf and metformin exposure.
| 2538861 | ecrin-mdr-crc
Project description:Interventions: Subjects will be randomly allocated to blinded treatment with cimetidine during cycle one of oxaliplatin treatment then crossover to placebo treatment in cycle two, or will receive the same blinded treatments in the opposite sequence. Cimetidine or placebo capsules will be given as a single oral dose 0.5 hours prior to commencement of the oxaliplatin infusion.
In the dose-escalation phase of the trial, the dose of cimetidine will be increased sequentially in cohorts of three patients using a traditional 3+3+3 rule-based oncology phase I clinical trial design. The dose escalation phase of the trial will explore cimetidine treatment given concurrently with oxaliplatin at six dose-levels (200, 400, 800, 1200, 1600 and 2000 mg).
Following treatment of the first cohort of three patients at a given dose-level, three main possibilities exist: 1) if all three patients have DLT, then that dose-level will be declared the MTD and the next cohort of three patients will be treated at the next lowest dose-level; 2) if none of three patients have DLT, then the next cohort of three patients will be treated with the next highest dose level, and; 3) if one or two of three patients had DLT, then the next cohort of three patients will be treated at the same dose-level to expand that dose level. Dose escalation may stop when one or more of the following has occurred: 1) the maximally tolerated dose of cimetidine is reached; 2) cimetidine was found to significantly alter the pharmacokinetics of oxaliplatin, or; 3) the recommended dose for cohort expansion of cimetidine has been reached.
After identifying a cimetidine dose recommended for cohort expansion, 30 patients will be recruited to receive a fixed dose of cimetidine using the crossover design to generate clinical p
Primary outcome(s): Plasma pharmacokinetics of intact oxaliplatin defined by plasma concentration at steady-state (Css) and area under the plasma concentration-versus-time curve (AUC) of intact oxaliplatin [Single plasma sample will be collected and processed at the end of infusion on Day 1 of Cycles 1 and 2 for the main study.
For the optional sub-study, 16 plasma samples will be collected at pre-infusion, at 20, 40, 60 and 90 minutes after the start of the oxaliplatin infusion, at the end of the infusion and 5, 10, 20, 30, 60, 120, 180, 300 minutes, 24 and 72 hours, thereafter.]
Study Design: Purpose: Treatment; Allocation: Randomised controlled trial
| 2468642 | ecrin-mdr-crc
Project description:This model is supplementary material of publication "Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues"
by Darta Maija Zake, Linda Zaharenko, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
This is a whole-body model representing the pharmacokinetics of metformin in the mouse body. The model is in the form of ordinary differential equations and describes metformin concentration in 20 compartments.
The model consists of 20 compartments (“Compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, intestine, kidney, heart, fat, muscle, brain, lungs, stomach, liver, portal vein, remainder urine and feces). Body weight and the weight of all compartments is expressed as a volume in mL and for the calculations it is assumed that 1mL = 1g. The volumes of most compartments are calculated as a fraction of the body weight/volume, and the fractions are determined from literature data, the volumes of the stomach lumen and intestine lumen are fixed and do not change depending on the body weight. Similarly, the volume of external urine and feces is set to 1mL, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 20 species (“Species” in COPASI model) that correspond to the metformin concentrations in the 20 compartments. The initial concentrations for all the species are 0 nmol/mL as metformin is not produced in the body and can only be detected after dose administration.
The model consists of 33 reactions – they describe the transport processes of metformin in the body. The reactions include local parameters that are involved only in that particular reaction and global parameters – parameters that are used in multiple reactions or are calculated depending on another parameter e.g. scale-up coefficients.
The model consists of 52 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing metformin dose – either in peroral (Metformin Dose in Lumen in mg) or intravenous (Metformin Dose in Plasma in mg).
2.Parameter describing mice physiology – body weight (in mL), cardiac output, blood flow to different compartments described as Q”compartment_name” (for example Qliver describes blood flow to the liver compartment). Qgfr refers to the glomerular filtration rate.
3.Tissue:plasma partition coefficients (Ktp) that are necessary for the scale-up to humans.
4.Parameters involved in the calculation of metformin amount in mg, these parameters are named mg”Compartment_name” (for example mgLiver describes the metformin amount in mg in the liver tissues).
The time points of dose release are defined as “events” in COPASI and can be changed as necessary.
Time course simulations can be accessed through the section “Time Course” in this section the time duration and intervals can be changed. When time-course simulations are run three plots are created – Metformin amount in the 20 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots). Also plotting the species result after 0.5 hours will reproduce the literature results.
2024-09-02 | BIOMD0000001039 | BioModels
Project description:This model is supplementary material of publication "Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues"
by Darta Maija Zake, Linda Zaharenko, Janis Kurlovics, Vitalijs Komasilovs, Janis Klovins and Egils Stalidzans.
The model is pre-set for simulation of a single peroral dose.
This is a whole-body model representing the pharmacokinetics of metformin in the mouse body. The model is in the form of ordinary differential equations and describes metformin concentration in 20 compartments.
The model consists of 20 compartments (“Compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, intestine, kidney, heart, fat, muscle, brain, lungs, stomach, liver, portal vein, remainder urine and feces). Body weight and the weight of all compartments is expressed as a volume in mL and for the calculations it is assumed that 1mL = 1g. The volumes of most compartments are calculated as a fraction of the body weight/volume, and the fractions are determined from literature data, the volumes of the stomach lumen and intestine lumen are fixed and do not change depending on the body weight. Similarly, the volume of external urine and feces is set to 1mL, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 20 species (“Species” in COPASI model) that correspond to the metformin concentrations in the 20 compartments. The initial concentrations for all the species are 0 nmol/mL as metformin is not produced in the body and can only be detected after dose administration.
The model consists of 33 reactions – they describe the transport processes of metformin in the body. The reactions include local parameters that are involved only in that particular reaction and global parameters – parameters that are used in multiple reactions or are calculated depending on another parameter e.g. scale-up coefficients.
The model consists of 52 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing metformin dose – either in peroral (Metformin Dose in Lumen in mg) or intravenous (Metformin Dose in Plasma in mg).
2.Parameter describing mice physiology – body weight (in mL), cardiac output, blood flow to different compartments described as Q”compartment_name” (for example Qliver describes blood flow to the liver compartment). Qgfr refers to the glomerular filtration rate.
3.Tissue:plasma partition coefficients (Ktp) that are necessary for the scale-up to humans.
4.Parameters involved in the calculation of metformin amount in mg, these parameters are named mg”Compartment_name” (for example mgLiver describes the metformin amount in mg in the liver tissues).
The time points of dose release are defined as “events” in COPASI and can be changed as necessary.
Time course simulations can be accessed through the section “Time Course” in this section the time duration and intervals can be changed. When time-course simulations are run three plots are created – Metformin amount in the 20 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots).
2024-09-02 | BIOMD0000001027 | BioModels
Project description:This model is supplementary material of publication "Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues"
by Darta Maija Zake, Linda Zaharenko, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
This is a whole-body model representing the pharmacokinetics of metformin in the human body. The model is in the form of Ordinary differential equations and describes metformin concentration in 21 compartments.
The model consists of 21 compartments (“compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, red blood cells, intestine, kidney, heart, fat, muscle, brain, lungs, stomach, liver, portal vein, remainder, urine and feces). Body weight and the weight of all compartments is expressed as a volume in mL and for the calculations it is assumed that 1mL = 1g. The volumes of most compartments are calculated as a fraction of the body weight/volume, and the fractions are determined from literature data, the volumes of the stomach lumen and intestine lumen are fixed and do not change depending on the body weight. Similarly, the volume of external urine and feces is set to 1L, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 21 species (“species” in COPASI model) that correspond to the metformin concentrations in the 21 compartments. The initial concentrations for all the species are 0 nmol/mL as metformin is not produced in the body and can only be detected after dose administration.
The model consists of 35 reactions – they describe the transport processes of metformin in the body. The reactions include local parameters that are involved only in that particular reaction and global parameters – parameters that are used in multiple reactions or are calculated depending on another parameter e.g. scale-up coefficients.
The model consists of 62 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing peroral metformin dose (Metformin Dose in Lumen in mg).
2.Parameter describing human physiology – body weight (in mL), cardiac output, blood flow to different compartments described as Q”compartment_name” (for example Qliver describes blood flow to the liver compartment). Qgfr refers to the glomerular filtration rate.
3.Parameters involved in the scale-up of the model
•Tissue:plasma partition coefficients (Ktp) that were estimated in the mice model.
•Kidney coefficient that is used for the scale-up of metformin elimination and is involved in the calculation of the rate parameters in the reactions “13.4. KidneyPlasma -> KidneyTissue” and “13.5. KidneyTissue -> KidneyTubular”. This parameter was determined using parameter estimation.
•Intestine coefficient that is involved in the calculation of the intestinal reaction rates of the reactions (03.2. IntestineLumen -> Enterocytes (PMAT OCT3), 03.3. Enterocytes -> IntestineVascular (OCT1), 03.4. IntestineLumen -> IntestineVascular (Saturable), 03.6. IntestineLumen -> Enterocytes (Diffusion) , 03.7. IntestineLumen -> IntestineVascular (Diffusion)). The parmaeters for these reactions are taken from Proctor publication and the intectine coefficient is used for the scale-up from the cell-culture to the human intestine.
4.Parameters involved in the calculation of metformin amount in mg, these parameters are named mg”Compartment_name” (for example mgLiver describes the metformin amount in mg in the liver tissues).
The time points of dose release are defined as “events” in COPASI and can be changed as necessary. The current model has 14 events and is set for a multiple-dose regimen for 7-day long twice-daily metformin administration.
Time course simulations can be accessed through the section “Time Course” in this section the time duration and intervals can be changed. When time-course simulations are run three plots are created – Metformin amount in the 21 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots). The time-course also includes multiple "Sliders" that allow to easily change 3 parameters - "Body Weight", "Cardiac Output", "Metformin Dose in Lumen in mg".
2024-09-02 | BIOMD0000001029 | BioModels
Project description:This model is supplementary material of publication "Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues"
by Darta Maija Zake, Linda Zaharenko, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
This is a whole-body model representing the pharmacokinetics of metformin in the human body. The model is in the form of Ordinary differential equations and describes metformin concentration in 21 compartments.
The model consists of 21 compartments (“compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, red blood cells, intestine, kidney, heart, fat, muscle, brain, lungs, stomach, liver, portal vein, remainder, urine and feces). Body weight and the weight of all compartments is expressed as a volume in mL and for the calculations it is assumed that 1mL = 1g. The volumes of most compartments are calculated as a fraction of the body weight/volume, and the fractions are determined from literature data, the volumes of the stomach lumen and intestine lumen are fixed and do not change depending on the body weight. Similarly, the volume of external urine and feces is set to 1L, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 21 species (“species” in COPASI model) that correspond to the metformin concentrations in the 21 compartments. The initial concentrations for all the species are 0 nmol/mL as metformin is not produced in the body and can only be detected after dose administration.
The model consists of 35 reactions – they describe the transport processes of metformin in the body. The reactions include local parameters that are involved only in that particular reaction and global parameters – parameters that are used in multiple reactions or are calculated depending on another parameter e.g. scale-up coefficients.
The model consists of 62 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing peroral metformin dose (Metformin Dose in Lumen in mg).
2.Parameter describing human physiology – body weight (in mL), cardiac output, blood flow to different compartments described as Q”compartment_name” (for example Qliver describes blood flow to the liver compartment). Qgfr refers to the glomerular filtration rate.
3.Parameters involved in the scale-up of the model
•Tissue:plasma partition coefficients (Ktp) that were estimated in the mice model.
•Kidney coefficient that is used for the scale-up of metformin elimination and is involved in the calculation of the rate parameters in the reactions “13.4. KidneyPlasma -> KidneyTissue” and “13.5. KidneyTissue -> KidneyTubular”. This parameter was determined using parameter estimation.
•Intestine coefficient that is involved in the calculation of the intestinal reaction rates of the reactions (03.2. IntestineLumen -> Enterocytes (PMAT OCT3), 03.3. Enterocytes -> IntestineVascular (OCT1), 03.4. IntestineLumen -> IntestineVascular (Saturable), 03.6. IntestineLumen -> Enterocytes (Diffusion) , 03.7. IntestineLumen -> IntestineVascular (Diffusion)). The parmaeters for these reactions are taken from Proctor publication and the intectine coefficient is used for the scale-up from the cell-culture to the human intestine.
4.Parameters involved in the calculation of metformin amount in mg, these parameters are named mg”Compartment_name” (for example mgLiver describes the metformin amount in mg in the liver tissues).
The time points of dose release are defined as “events” in COPASI and can be changed as necessary. The current model has 14 events and is set for a multiple-dose regimen for 7-day long twice-daily metformin administration.
Time course simulations can be accessed through the section “Time Course” in this section the time duration and intervals can be changed. When time-course simulations are run three plots are created – Metformin amount in the 21 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots). The time-course also includes multiple "Sliders" that allow to easily change 3 parameters - "Body Weight", "Cardiac Output", "Metformin Dose in Lumen in mg".
2024-09-02 | BIOMD0000001028 | BioModels
Project description:Administration of metformin increases healthspan and lifespan in model systems and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70-year-old participants (n=14), in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed-meal challenge test was performed. As expected, metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and non-metabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR & SREBP signaling, mitochondrial fatty acid oxidation and collagen trimerization in adipose. While each tissue had, a signature reflecting its own function, we identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFß1 and miRNA-29b, that may explain tissue-specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and non-metabolic effects linked to aging. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways. Key words: Aging, biguanides, gene expression, metabolism, upstream regulators
2017-12-12 | GSE107894 | GEO
Project description:Intervention name : Lonsurf combination tablet T15/T20
INN of the intervention : trifluridine + tipiracil hydrochloride
Dosage And administration of the intervention : Usually, the standard doses below are defined as the initial dose (single dose) for adults according to body surface area (approximately 35 mg of Trifluridine/m2/dose). Lonsurf is administered twice daily, after breakfast and after the evening meal, for 5 consecutive days, followed by a 2-day rest. After repeating this twice, follows a 14-day rest. This is one cycle of the regimen and it shall be repeated.
Study Design: Postmarketing surveillance
| 2611187 | ecrin-mdr-crc
Project description:Interventions: investigational material(s)
Generic name etc : Lonsurf combination tablet T15/T20
INN of investigational material : trifluridine + tipiracil hydrochloride
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Usually, the standard doses below are defined as the initial dose (single dose) for adults according to body surface area (approximately 35 mg of Trifluridine/m2/dose). Lonsurf is administered twice daily, after breakfast and after the evening meal, for 5 consecutive days, followed by a 2-day rest. After repeating this twice, follows a 14-day rest. This is one cycle of the regimen and it shall be repeated.
Study Design: Postmarketing surveillance
| 97953 | ecrin-mdr-crc
Project description:Alzheimer’s dementia (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics, however, comprehensive plasma profiling is challenging due to the large dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood-brain barrier and may provide a source for AD related biomarkers. We investigated plasma-derived EV proteins for biomarkers towards AD diagnostics from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography - tandem mass spectrometry (LC-MS/MS). EV enrichment was performed using a double centrifugation of 100,000 × g, 1h, 4°C with a wash of the pellet. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A group of proteins was identified discriminating Con and AD (AUC: 0.91, CI: 0.67-1.00) with ORM2 (AUC: 1.00, CI: 1.00-1.00), RBP4 (AUC: 0.99, CI: 0.95-1.00), and HYDIN (AUC: 0.89, CI: 0.72-1.00) found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible biomarkers for AD. Some of the MCI patients, with similar protein profiles as the AD group progressed to AD within a 2-year timespan.
2022-02-16 | PXD024216 | Pride