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A proof of concept reinforcement learning based tool for non parametric population pharmacokinetics workflow optimization
We present the selected discretization for the action and the state space. SARSA (State-Action-Reward-State-Action) was selected as the RL algorithm to use, configured with a window of 1000 episodes with and a limit of 30 actions per episode. SARSA was configured to control an interface to the Non-Parametric Optimal Design algorithm, that was actually performing the parameter optimization.The Reinforcement Learning (RL) based agent managed to obtain the same likelihood and number of support points, with a distribution similar to the reported in the original paper. The total amount of time used by the train the agent was 5....
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 7, 2022 Category: Drugs & Pharmacology Source Type: research

Pharmacometric modeling of drug adverse effects: an application of mixture models in schizophrenia spectrum disorder patients treated with clozapine
AbstractClozapine has superior efficacy to other antipsychotics yet is underutilized due to its adverse effects, such as neutropenia, weight gain, and tachycardia. The current investigation aimed to introduce a pharmacometric approach to simultaneously model drug adverse effects, with examples from schizophrenia spectrum patients receiving clozapine. The adverse drug effects were represented as a function of time by incorporating a mixture model to describe individual susceptibility to the adverse effects. Applications of the proposed method were presented by analyzing retrospective data from patients ’ medical records i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 15, 2022 Category: Drugs & Pharmacology Source Type: research

Pharmacometric model of agalsidase –migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule
AbstractRecently, a new mechanism of drug –drug interaction (DDI) was reported between agalsidase, a therapeutic protein, and migalastat, a small molecule, both of which are treatment options of Fabry disease. Migalastat is a pharmacological chaperone that stabilizes the native form of both endogenous and exogenous agalsidase. In Fabry pa tients co-administrated with agalsidase and migalastat, the increase in active agalsidase exposure is considered a pharmacokinetic effect of agalsidase infusion but a pharmacodynamic effect of migalastat administration, which makes this new DDI mechanism even more interesting. To quanti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 14, 2022 Category: Drugs & Pharmacology Source Type: research

The Finite Absorption Time (FAT) concept en route to PBPK modeling and pharmacometrics
AbstractThe concept of Finite Absorption Time (FAT) for oral drug administration is set to affect pharmacokinetic analyses, Physiologically-based Pharmacokinetics simulations, and Pharmacometrics. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 11, 2022 Category: Drugs & Pharmacology Source Type: research

Individualized optimization of colistin loading doses
In this study we develop a framework to determine two key parameters for the loading dose regimen: (1) the optimal dose according to the characteristics (renal function and weight) of the patient; (2) the waiting time before the maintenance dose. Based on a previous PK model, our framework allows a fast parameter sweep so as to select optimal loading dose and waiting time minimizing the deviation between the plasma concentration and a target value. The results showed that patients presenting low creatinine clearance (CrCL) should receive a lower CMS loading dose with longer interval to start maintenance treatment to avoid ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 2, 2022 Category: Drugs & Pharmacology Source Type: research

Accelerating robust plausible virtual patient cohort generation by substituting ODE simulations with parameter space mapping
AbstractThe generation of plausible virtual patients (VPs) is an important step in most quantitative systems pharmacology (QSP) workflows, which requires time-intensive solving of ordinary differential equations (ODEs). However, non-physiological profiles of outputs of interest (OoI) are frequently produced, and additional acceptance/rejection steps are needed for comparing and removing VPs with predicted values outside a pre-defined range. Here, a new approach is developed to accelerate the acceptance/rejection steps by leveraging patterns of parameter associations with OoI. In most models, some parameters are monotonic w...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 31, 2022 Category: Drugs & Pharmacology Source Type: research

Modeling of the effect of cerebrospinal fluid flow modulation on locally delivered drugs in the brain
AbstractCerebrospinal fluid (CSF) plays a vital role in maintaining brain homeostasis and recent research has focused on elucidating the role that convective flow of CSF plays in brain health. This paper describes a computational compartmental model of how CSF dynamics affect drug pharmacokinetics in the rat brain. Our model implements a local, sustained release approach for drug delivery to the brain. Simulation outputs highlight the potential for modulating CSF flow to improve overall drug pharmacokinetics in the central nervous system and suggest that concomitant CSF modulation and optimized drug release rates from impl...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 25, 2022 Category: Drugs & Pharmacology Source Type: research

Physiologically-based pharmacokinetic model for pulmonary disposition of protein therapeutics in humans
In this study we fill that gap by extending the cross-species two-pore physiologically-based pharmacokinetic (PBPK) platform with more detailed respiratory tract that includes the airways and alveolar space with epithelial lining fluid. We parameterize the paracellular and FcRn-facilitated exchange pathways between the epithelial lining fluid and lung interstitial space by building a mechanistic model for the exchange between the two. The optimized two-pore PBPK model described pulmonary exposure of several systemically dosed mAbs for which data is available and is also in agreement with the observed levels of endogenous I...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 20, 2022 Category: Drugs & Pharmacology Source Type: research