On inductive biases for the robust and interpretable prediction of drug concentrations using deep compartment models
In this study, we build on the deep compartment model (DCM) architecture by introducing constraints that guide the model to explore more physiologically realistic solutions. Using a simulation study, we show that constraints improve robustness in sparse data settings. Additionally, predicted concentration –time curves took on more realistic shapes compared to unconstrained models. Next, we propose the use of multi-branch networks, where each covariate can be connected to specific PK parameters, to reduce the propensity of models to learn spurious effects. Another benefit of this architecture is t hat covariate effects ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 26, 2024 Category: Drugs & Pharmacology Source Type: research

Maximum a posteriori Bayesian methods out-perform non-compartmental analysis for busulfan precision dosing
In conclusion, although AUC estimates between the two methods showed good correlation, in a simulated study, MAP lead to higher target attainment. When changing from one method to another, or changing infusion duration and oth er factors, optimum estimated exposure targets may require adjusting to maintain a consistent exposure. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 23, 2024 Category: Drugs & Pharmacology Source Type: research

Oral docetaxel plus encequidar – A pharmacokinetic model and evaluation against IV docetaxel
Conclusion: The study demonstrates the benefits of MIDD using oDox + E as a mot ivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV doc etaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 19, 2024 Category: Drugs & Pharmacology Source Type: research

Predicting efficacy assessment of combined treatment of radiotherapy and nivolumab for NSCLC patients through virtual clinical trials using QSP modeling
AbstractNon-Small Cell Lung Cancer (NSCLC) remains one of the main causes of cancer death worldwide. In the urge of finding an effective approach to treat cancer, enormous therapeutic targets and treatment combinations are explored in clinical studies, which are not only costly, suffer from a shortage of participants, but also unable to explore all prospective therapeutic solutions. Within the evolving therapeutic landscape, the combined use of radiotherapy (RT) and checkpoint inhibitors (ICIs) emerged as a promising avenue. Exploiting the power of quantitative system pharmacology (QSP), we undertook a study to anticipate ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 17, 2024 Category: Drugs & Pharmacology Source Type: research

An industry perspective on current QSP trends in drug development
This article reflects on all these questions, in particular addressing those audiences with limited line-of-sight into the drug industry decision-making machinery. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 5, 2024 Category: Drugs & Pharmacology Source Type: research

Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis
AbstractBrepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Inde...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 3, 2024 Category: Drugs & Pharmacology Source Type: research

Fourteenth American Conference on Pharmacometrics (ACoP14) – Innovation and Diversity: Redefining Pharmacometrics
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 28, 2024 Category: Drugs & Pharmacology Source Type: research

Subgroup identification-based model selection to improve the predictive performance of individualized dosing
AbstractCurrently, model-informed precision dosing uses one population pharmacokinetic model that best fits the target population. We aimed to develop a subgroup identification-based model selection approach to improve the predictive performance of individualized dosing, using vancomycin in neonates/infants as a test case. Data from neonates/infants with at least one vancomycin concentration was randomly divided into training and test dataset. Population predictions from published vancomycin population pharmacokinetic models were calculated. The single best-performing model based on various performance metrics, including m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 24, 2024 Category: Drugs & Pharmacology Source Type: research

A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics
AbstractProtein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic ’s physicochemical parameters and its corresponding ADME properties. The model’s compound-specific input includes molecular weight, m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 24, 2024 Category: Drugs & Pharmacology Source Type: research

Subgroup identification-based model selection to improve the predictive performance of individualized dosing
AbstractCurrently, model-informed precision dosing uses one population pharmacokinetic model that best fits the target population. We aimed to develop a subgroup identification-based model selection approach to improve the predictive performance of individualized dosing, using vancomycin in neonates/infants as a test case. Data from neonates/infants with at least one vancomycin concentration was randomly divided into training and test dataset. Population predictions from published vancomycin population pharmacokinetic models were calculated. The single best-performing model based on various performance metrics, including m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 24, 2024 Category: Drugs & Pharmacology Source Type: research