Search results for " modelling"

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for for…

2013

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the e…

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and ov…

2016

Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters.Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exer…

Oral biopharmaceutics tools – Time for a new initiative – An introduction to the IMI project OrBiTo

2013

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharm…

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysin…

2016

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded “bottom-up” anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on pe…

Predicting Pharmacokinetics of Multisource Acyclovir Oral Products Through Physiologically Based Biopharmaceutics Modeling.

2021

Abstract Highly variable disposition after oral ingestion of acyclovir has been reported, although little is known regarding the underlying mechanisms. Different studies using the same reference product (Zovirax ®) showed that Cmax and AUC were respectively 44 and 35% lower in Saudi Arabians than Europeans, consistent with higher frequencies of reduced-activity polymorphs of the organic cation transporter (OCT1) in Europeans. In this study, the contribution of physiology (i.e., OCT1 activity) to the oral disposition of acyclovir immediate release (IR) tablets was hypothesized to be greater than dissolution. The potential role of OCT1 was studied in a validated physiologically-based biopharm…

Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making

2021

Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course o…

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

2020

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mo…

OPTIMIZING STOCHASTIC SUSCEPTIBILITY MODELLING FOR DEBRIS FLOW LANDSLIDES: PIXEL SIZE EFFECTS, PROBLEMS IN CHRONO-VALIDATION, 2D SPATIALLY DISTRIBUTE…

Effect of spatial distribution of impurity ions on the signal of ‘C/O monitor for Wendelstein 7-X’ - an indicator of plasma wall interactions

2022

The ‘C/O monitor’ is a dedicated diagnostic system designed to monitor light impurities (B, C, N and O) in the Wendelstein 7-X (W7-X) stellarator. Its main goal is to provide fast (∼1 ms) information about the impurity level which is measured from a large plasma volume (high throughput). Its first subsystem dedicated to measure Lyman-α lines of H-like carbon (C5+ − 3.4 nm – used as PFC material) and oxygen (O7+ − 1.9 nm – common impurity absorbed by inner vessels’ walls) is going to be commissioned during the next Operational Phase of W7-X. Since the radiated photon intensity of a given impurity depends strongly on plasma kinetic parameters (Te, ne) and impurity transport, it is important t…

Polarity-reversal subduction zone initiation triggered by buoyant plateau obstruction

2022

Abstract Oceanic lithosphere worldwide is younger than ca. 200 Myr, suggesting that it must have been globally recycled by the recurrent formation of new subduction zones since the existence of subduction on Earth. However, postulated subduction zone initiation processes remain difficult to explain in many cases, and the specific geodynamic conditions under which these might occur are still largely unknown. We here use numerical models driven by the internal force balance of a subduction system to better understand the (geo)dynamics governing (intra-oceanic) polarity-reversal subduction zone initiation. This initiation mode assumes that the birth of a new subduction zone could be triggered …