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Development of a multiscale mechanistic modeling framework integrating differential cellular kinetics of CAR T ‐cell subsets and immunophenotypes in cancer patients
AbstractChimeric antigen receptor (CAR) T-cell subsets and immunophenotypic composition of the pre-infusion product, as well as their longitudinal changes following infusion, are expected to affect CAR T-cell expansion, persistence, and clinical outcomes. Herein, we sequentially evolved our previously described cellular kinetic-pharmacodynamic (CK-PD) model to incorporate CAR T-cell product-associated attributes by utilizing published preclinical and clinical datasets from two affinity variants (FMC63 and CAT19 scFv) anti-CD19 CAR T-cells. In step 1, a unified cell-level PD model was used to simultaneously characterize the...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 18, 2023 Category: Drugs & Pharmacology Authors: Ahmed M. Salem, Ganesh M. Mugundu, Aman P. Singh Tags: ARTICLE Source Type: research

Improving pharmacometrics analysis efficiency using DataCheQC: An interactive, Shiny ‐based app for quality control of pharmacometrics datasets
AbstractDataCheQC is an interactive application based on the R Shiny framework developed for the purposes of performing quality control (QC) checks on pharmacometric datasets, and thereby supporting the implementation of model-informed drug development. Features include visual inspection of variables and data entries for errors and/or anomalies, and ensuring structural integrity through comparison with a dataset specification file. The app, which requires no programming knowledge to operate, allows the user to collect all findings into a summary report downloadable directly from the app itself. The source code for the app ...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 18, 2023 Category: Drugs & Pharmacology Authors: Or Dotan, Andrijana Radivojevic, Rajendra Singh Tags: TUTORIAL Source Type: research

Development and application of a PBPK modeling strategy to support antimalarial drug development
AbstractAs part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5  years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real-world development and c...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 17, 2023 Category: Drugs & Pharmacology Authors: Nada Abla, Eleanor Howgate, Karen Rowland ‐Yeo, Maurice Dickins, Mackenzie C. Bergagnini‐Kolev, Kuan‐Fu Chen, Savannah McFeely, Jennifer J. Bonner, Laura G. A. Santos, Nathalie Gobeau, Howard Burt, Zoe Barter, Hannah M. Jones, David Wes Tags: ARTICLE Source Type: research

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Source: CPT: Pharmacometrics and Systems Pharmacology - August 16, 2023 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Development and application of a PBPK modeling strategy to support antimalarial drug development
AbstractAs part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5  years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real-world development and c...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 16, 2023 Category: Drugs & Pharmacology Authors: Nada Abla, Eleanor Howgate, Karen Rowland ‐Yeo, Maurice Dickins, Mackenzie C. Bergagnini‐Kolev, Kuan‐Fu Chen, Savannah McFeely, Jennifer J. Bonner, Laura G. A. Santos, Nathalie Gobeau, Howard Burt, Zoe Barter, Hannah M. Jones, David Wes Tags: ARTICLE Source Type: research

Building an adaptive dose simulation framework to aid dose and schedule selection
AbstractEstablishing a dosing regimen that maximizes clinical benefit and minimizes side effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in-silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose-interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit.In this tutorial we pres...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 14, 2023 Category: Drugs & Pharmacology Authors: Richard Hooijmaijers, Ridhi Parasrampuria, Eleonora Marostica, Geraldine Ferron ‐Brady, Teun M. Post, Sandra A. G. Visser Tags: TUTORIAL Source Type: research

Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery ‐Åsberg Depression Rating Scale
AbstractIn clinical trials, Montgomery- Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase t...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 11, 2023 Category: Drugs & Pharmacology Authors: Marije E. Otto, Kirsten R. Bergmann, Marieke L. Kam, Kasper Recourt, Gabri ël E. Jacobs, Michiel J. Esdonk Tags: ARTICLE Source Type: research

Clinical decision support for chemotherapy ‐induced neutropenia using a hybrid pharmacodynamic/machine learning model
AbstractConsensus guidelines recommend use of granulocyte colony stimulating factor in patients deemed at risk of chemotherapy-induced neutropenia, however, these risk models are limited in the factors they consider and miss some cases of neutropenia. Clinical decision making could be supported using models that better tailor their predictions to the individual patient using the wealth of data available in electronic health records (EHRs). Here, we present a hybrid pharmacokinetic/pharmacodynamic (PKPD)/machine learning (ML) approach that uses predictions and individual Bayesian parameter estimates from a PKPD model to enr...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 10, 2023 Category: Drugs & Pharmacology Authors: Jasmine H. Hughes, Dominic M. H. Tong, Vanessa Burns, Bobby Daly, Pedram Razavi, Jaap J. Boelens, Srijib Goswami, Ron J. Keizer Tags: ARTICLE Source Type: research

Semimechanistic pharmacokinetic –pharmacodynamic model of tripegfilgrastim for pediatric patients after chemotherapy
This study aimed to establish a pharmacokinetic (PK) –pharmacodynamic (PD) model to explore the impact of chemotherapy and tripegfilgrastim on absolute neutrophil counts (ANCs) and to further propose a fixed-dose regimen in pediatric patients. Because neutrophils affect the clearance of tripegfilgrastim, the semimechanistic PK-PD model was developed simultaneously by using data from 40 healthy adults and 27 pediatric patients with solid tumors. Tripegfilgrastim PK and ANC dynamics were described with a pharmacodynamics-mediated drug disposition model assuming quasi-equilibrium with five transit compartments mimicking neu...
Source: CPT: Pharmacometrics and Systems Pharmacology - August 10, 2023 Category: Drugs & Pharmacology Authors: Soyoung Lee, Kyung Taek Hong, In ‐Jin Jang, Kyung‐Sang Yu, Hyoung Jin Kang, Jaeseong Oh Tags: ARTICLE Source Type: research