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A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis
AbstractSepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network of regulatory relationships was developed for key immune components associated with sepsis pathogenesis after TLR4 activation. Pe...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 19, 2022 Category: Drugs & Pharmacology Source Type: research

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson ’s disease: application to preladenant
AbstractThe clinical impact of therapeutic interventions in Parkinson ’s disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion ch...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 9, 2022 Category: Drugs & Pharmacology Source Type: research

Impact of model misspecification on model-based tests in PK studies with parallel design: real case and simulation studies
This article evaluates the performance of pharmacokinetic (PK) equivalence testing between two formulations of a drug through the Two-One Sided Tests (TOST) by a model-based approach (MB-TOST), as an alternative to the classical non-compartmental approach (NCA-TOST), for a sparse design with a few time points per subject. We focused on the impact of model misspecification and the relevance of model selection for the reference data. We first analysed PK data from phase I studies of gantenerumab, a monoclonal antibody for the treatment of Alzheimer ’s disease. Using the original rich sample data, we compared MB-TOST to NCA...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 16, 2022 Category: Drugs & Pharmacology Source Type: research

PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data
The objective of this manuscript was to validate a physiologically-based pharmacokinetic (PBPK) model developed to characterize brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) using novel large-pore microdialysis data generated in mice. To support this objective, brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody was measured in mice following intraperitoneal (IP) administration. This antibody has no binding in mice. In addition, our recently published mouse brain PK data generated following intravenous (IV) and IP administration of trastuzumab in mice, and other published PK data for brain di...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 10, 2022 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial
This report reviews evidence for drugs with SRB features, describes previous pharmacokinetic/pharmacodynamic (PK/PD) modeling efforts of several such drugs, provides a tutorial on the mathematics and properties of SRB models, demonstrates applications of SRB models to additional compounds, and compares PK/PD fittings of SRB with other mechanistic models. We identified and summarized 52 drugs with in vitro-confirmed SRB from a PubMed literature search. Simulations with a SRB model and observed PK/PD profiles showed delayed and prolonged responses and that increasing doses/kon or decreasingkoff led to greater expected maximu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 30, 2022 Category: Drugs & Pharmacology Source Type: research

Towards a comprehensive assessment of QSP models: what would it take?
AbstractQuantitative Systems Pharmacology (QSP) has emerged as a powerful ensemble of approaches aiming at developing integrated mathematical and computational models elucidating the complex interactions between pharmacology, physiology, and disease. As the field grows and matures its applications expand beyond the boundaries of research and development and slowly enter the decision making and regulatory arenas. However, widespread acceptance and eventual adoption of a new modeling approach requires assessment criteria and quantifiable metrics that establish credibility and increase confidence in model predictions. QSP aim...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 13, 2022 Category: Drugs & Pharmacology Source Type: research

Current practices for QSP model assessment: an IQ consortium survey
This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 11, 2022 Category: Drugs & Pharmacology Source Type: research