CPT: Pharmacometrics and Systems Pharmacology This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Population pharmacokinetics of intraperitoneal irinotecan and SN ‐38 in patients with peritoneal metastases from colorectal origin
AbstractPeritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was develope...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 18, 2024 Category: Drugs & Pharmacology Authors: Pascale C. S. Rietveld, Sebastiaan D. T. Sassen, Niels A. D. Guchelaar, Ruben A. G. van Eerden, Nadine L. de Boer, Teun B. M. van den Heuvel, Jacobus W. A. Burger, Ron H. J. Mathijssen, Birgit C. P. Koch, Stijn L. W. Koolen Tags: ARTICLE Source Type: research

Tumor growth and overall survival modeling to support decision making in phase Ib/II trials: A comparison of the joint and two ‐stage approaches
AbstractModel-based tumor growth inhibition (TGI) metrics are increasingly used to predict overall survival (OS) data in Phase III immunotherapy clinical trials. However, there is still a lack of understanding regarding the differences between two-stage or joint modeling methods to leverage Phase I/II trial data and help early decision-making. A recent study showed that TGI metrics such as the tumor growth rate constantKG may have good operating characteristics as early endpoints. This previous study used a two-stage approach that is easy to implement and intuitive but prone to bias as it does not account for the relations...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 17, 2024 Category: Drugs & Pharmacology Authors: Mathilde Marchand, Antonio Gon çalves, François Mercier, Pascal Chanu, Jin Y. Jin, Jérémie Guedj, René Bruno Tags: ARTICLE Source Type: research

Population pharmacokinetics and exposure –response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study
AbstractPolatuzumab vedotin is a CD79b-directed antibody –drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse la rge B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure–response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful rela...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 16, 2024 Category: Drugs & Pharmacology Authors: Rong Deng, Leonid Gibiansky, Tong Lu, Christopher R. Flowers, Laurie H. Sehn, Qi Liu, Priya Agarwal, Michael Z. Liao, Randall Dere, Calvin Lee, Gabriel Man, Jamie Hirata, Chunze Li, Dale Miles Tags: ARTICLE Source Type: research

RPEM: Randomized Monte Carlo parametric expectation maximization algorithm
AbstractInspired from quantum Monte Carlo, by sampling discrete and continuous variables at the same time using the Metropolis –Hastings algorithm, we present a novel, fast, and accurate high performance Monte Carlo Parametric Expectation Maximization (MCPEM) algorithm. We named it Randomized Parametric Expectation Maximization (RPEM). We compared RPEM with NONMEM's Importance Sampling Method (IMP), Monolix's Stochastic A pproximation Expectation Maximization (SAEM), and Certara's Quasi-Random Parametric Expectation Maximization (QRPEM) for a realistic two-compartment voriconazole model with ordinary differential equatio...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 16, 2024 Category: Drugs & Pharmacology Authors: Rong Chen, Alan Schumitzky, Alona Kryshchenko, Keith Nieforth, Michael Tomashevskiy, Shuhua Hu, Romain Garreau, Julian Otalvaro, Walter Yamada, Michael N. Neely Tags: ARTICLE Source Type: research

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Source: CPT: Pharmacometrics and Systems Pharmacology - April 13, 2024 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Construction of a prognostic model based on memory CD4+ T cell –associated genes for lung adenocarcinoma and its applications in immunotherapy
In this study, using the cell-type identification by estimating relative subsets of RNA transcripts algorithm, we analyzed immune cell composition and patient survival in LUAD. Weighted gene coexpression network analysis helped identify memory CD4+ T cell –associated gene modules. Combined with module genes, a five-gene LUAD prognostic risk model (HOXB7,MELTF,ABCC2,GNPNAT1, andLDHA) was constructed by regression analysis. The model was validated using the GSE31210 data set. The validation results demonstrated excellent predictive performance of the risk scoring model. Correlation analysis was conducted between the clinic...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 10, 2024 Category: Drugs & Pharmacology Authors: Yong Li, Xiangli Ye, Huiqin Huang, Rongxiang Cao, Feijian Huang, Limin Chen Tags: ARTICLE Source Type: research

Physiologically based pharmacokinetics modeling and transporter proteomics to predict systemic and local liver and muscle disposition of statins
AbstractStatins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity. To bridge this gap, we used physiologically based pharmacokinetic (PBPK) modeling to predict intracellular concentrations of statins. Quantitative data on transpor...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 5, 2024 Category: Drugs & Pharmacology Authors: Luna Prieto  Garcia, Anna Vildhede, Pär Nordell, Christine Ahlström, Ahmed B. Montaser, Tetsuya Terasaki, Hans Lennernäs, Erik Sjögren Tags: ARTICLE Source Type: research

Covariate modeling in pharmacometrics: General points for consideration
AbstractModeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International So...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 3, 2024 Category: Drugs & Pharmacology Authors: Kinjal Sanghavi, Jakob Ribbing, James A. Rogers, Mariam A. Ahmed, Mats O. Karlsson, Nick Holford, Estelle Chasseloup, Malidi Ahamadi, Kenneth G. Kowalski, Susan Cole, Essam Kerwash, Janet R. Wade, Chao Liu, Yaning Wang, Mirjam N. Trame, Hao Tags: REVIEW Source Type: research

Joint modeling of tumor dynamics and progression ‐free survival in advanced breast cancer: Leveraging data from amcenestrant early phase I–II trials
AbstractA joint modeling framework was developed using data from 75 patients of early amcenestrant phase I –II AMEERA-1-2 dose escalation and expansion cohorts. A semi-mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure-driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of tre atment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of am...
Source: CPT: Pharmacometrics and Systems Pharmacology - April 2, 2024 Category: Drugs & Pharmacology Authors: Marc Cerou, Hoai ‐Thu Thai, Laure Deyme, Sophie Fliscounakis‐Huynh, Emmanuelle Comets, Patrick Cohen, Sylvaine Cartot‐Cotton, Christine Veyrat‐Follet Tags: ARTICLE Source Type: research

Clinical pharmacokinetics of leriglitazone and a translational approach using PBPK modeling to guide the selection of the starting dose in children
AbstractLeriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPAR γ) agonist that crosses the blood–brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engageme nt and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy...
Source: CPT: Pharmacometrics and Systems Pharmacology - March 29, 2024 Category: Drugs & Pharmacology Authors: Estefania Traver, Laura Rodr íguez‐Pascau, Uwe Meya, Guillem Pina, Silvia Pascual, Sonia Poli, David Eckland, Jeroen van de Wetering, Alice Ke, Andreas Lindauer, Marc Martinell, Pilar Pizcueta Tags: ARTICLE Source Type: research

Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy
AbstractDuchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder characterized by loss-of-function mutations in the gene encoding dystrophin. These mutations lead to progressive functional deterioration including muscle weakness, respiratory insufficiency, and musculoskeletal deformities. Three-dimensional gait analysis (3DGA) has been used as a tool to analyze gait pathology through the quantification of altered joint kinematics, kinetics, and muscle activity patterns. Among 3DGA indices, the Gait Profile Score (GPS), has been used as a sensitive overall measure to detect clinically relevant changes in gait...
Source: CPT: Pharmacometrics and Systems Pharmacology - March 28, 2024 Category: Drugs & Pharmacology Authors: Jiexin Deng, Fangli Liu, Zhifen Feng, Zhigang Liu Tags: ARTICLE Source Type: research

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression
AbstractTrastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU ®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bea ring mice carrying NCI-N87, Capan-1, JIMT-1, and MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T-DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX ...
Source: CPT: Pharmacometrics and Systems Pharmacology - March 27, 2024 Category: Drugs & Pharmacology Authors: Christina Vasalou, Theresa A. Proia, Laura Kazlauskas, Anna Przybyla, Matthew Sung, Srinivas Mamidi, Kim Maratea, Matthew Griffin, Rebecca Sargeant, Jelena Urosevic, Anton I. Rosenbaum, Jiaqi Yuan, Krishna C. Aluri, Diane Ramsden, Niresh Har Tags: ARTICLE Source Type: research