Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice.

Background: The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is an apical initiator of DNA damage response pathways. Several ATR inhibitors (ATRi) are in clinical development including berzosertib (formerly M6620, VX-970). Although clinical studies have examined plasma pharmacokinetics (PK) in humans, little is known regarding dose/exposure relationships and tissue distribution.

An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin.

The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere Insulin dose (22U or 20U). In the 30-120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin.

Long-term forecasting of a motor outcome following rehabilitation in chronic stroke via a hierarchical bayesian dynamic model.

Background: Given the heterogeneity of stroke, it is important to determine the best course of motor therapy for each patient, i.e., to personalize rehabilitation based on predictions of long-term outcomes.

Monoclonal Antibody Pharmacokinetics in Cynomolgus Monkeys Following Subcutaneous Administration: Physiologically Based Model Predictions from Physiochemical Properties.

An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous and subcutaneous administration. Significant associations were found between subcutaneous injection site degradation rate and the antibody's local positive charge of its complementarity-determining region (R = 0.

Analysis of Complex Absorption After Multiple Dosing: Application to the Interaction Between the P-glycoprotein Substrate Talinolol and Rifampicin.

Purpose: In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects.

Methods: A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation.

Results: The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.

Physiologically Based Modeling to Predict Monoclonal Antibody Pharmacokinetics in Humans from in vitro Physiochemical Properties.

A model-based framework is presented to predict monoclonal antibody (mAb) pharmacokinetics (PK) in humans based on measures of antibody physiochemical properties. A physiologically based pharmacokinetic (PBPK) model is used to explore the predictive potential of 14 assays designed to measure various antibody physiochemical properties, including nonspecific cell-surface interactions, FcRn binding, thermal stability, hydrophobicity, and self-association. Based on the mean plasma PK time course data of 22 mAbs from humans reported in the literature, we found a significant positive correlation (R = 0.

Open-source maximum a posteriori-bayesian dosing AdDS to current therapeutic drug monitoring: Adapting to the era of individualized therapy.

Recent updates in the therapeutic drug monitoring (TDM) guidelines for vancomycin have rekindled interest in maximum a posteriori-Bayesian (MAP-Bayesian) estimation of patient-specific pharmacokinetic parameters. To create a versatile infrastructure for MAP-Bayesian dosing of vancomycin or other drugs, a freely available, R-based software package, Advanced Dosing Solutions (AdDS), was created to facilitate clinical implementation of these improved TDM methods. The objective of this study was to utilize AdDS for pre- and post-processing of data in order to streamline the therapeutic management of vancomycin in healthy and obese veterans.

Characteristics of Passive Solute Transport across Primary Rat Alveolar Epithelial Cell Monolayers.

Primary rat alveolar epithelial cell monolayers (RAECM) were grown without (type I cell-like phenotype, RAECM-I) or with (type II cell-like phenotype, RAECM-II) keratinocyte growth factor to assess passive transport of 11 hydrophilic solutes. We estimated apparent permeability () in the absence/presence of calcium chelator EGTA to determine the effects of perturbing tight junctions on "equivalent" pores. across RAECM-I and -II in the absence of EGTA are similar and decrease as solute size increases.

An Analysis of Glucose Effectiveness in Subjects With or Without Type 2 Diabetes Hierarchical Modeling.

Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production, is an important mechanism maintaining normoglycemia. We conducted a minimal modeling analysis of glucose effectiveness at zero insulin () using intravenous glucose tolerance test data from subjects with type 2 diabetes (T2D, n=154) and non-diabetic (ND) subjects (n=343). A hierarchical statistical analysis was performed, which provided a formal mechanism for pooling the data from all study subjects, to yield a single composite population model that quantifies the role of subject specific characteristics such as weight, height, age, sex, and glucose tolerance.

A whole-body circulatory neutrophil model with application to predicting clinical neutropenia from in vitro studies.

A circulatory model of granulopoiesis and its regulation is presented that includes neutrophil trafficking in the lungs, liver, spleen, bone marrow, lymph nodes, and blood. In each organ, neutrophils undergo transendothelial migration from vascular to interstitial space, clearance due to apoptosis, and recycling via the lymphatic flow. The model includes cell cycling of progenitor cells in the bone marrow, granulocyte colony-stimulating factor (G-CSF) kinetics and its neutrophil regulatory action, as well as neutrophil margination in the blood.

The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens.

The drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Single agent therapy is insufficient for patients with late-stage tuberculosis because of resistance emergence.

Predicting Chemotherapy-Induced Neutropenia and Granulocyte Colony-Stimulating Factor Response Using Model-Based In Vitro to Clinical Translation.

The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug's mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model's drug effect parameters.

Biokinetic modeling of nanoparticle interactions with lung alveolar epithelial cells: uptake, intracellular processing, and egress.

Studies on health effects of engineered nanomaterials (ENMs) in the lung have provided information on ENM toxicity and translocation across airway and alveolar epithelial barriers. Various inhaled ENMs (e.g.

Population Pharmacokinetic Modeling of Vancomycin in Thai Patients With Heterogeneous and Unstable Renal Function.

Background: Vancomycin is widely used to treat gram-positive bacterial infections. However, given significant interpatient variability in its pharmacokinetics, maintaining plasma concentrations is difficult within its characteristically narrow therapeutic window. This is especially challenging in patients with unstable renal function.

The Efficiency, Efficacy, and Retention of Task Practice in Chronic Stroke.

In motor skill learning, larger doses of practice lead to greater efficacy of practice, lower efficiency of practice, and better long-term retention. Whether such learning principles apply to motor practice after stroke is unclear. Here, we developed novel mixed-effects models of the change in the perceived quality of arm movements during and following task practice.

Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling.

Use of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because of an incomplete understanding of fundamental mechanisms controlling mAb absorption from the SC site, and due to the limited translatability of preclinical studies. In this paper, we report on the development and evaluation of a whole-body physiologically-based model to predict mAb pharmacokinetics following SC administration. The circulatory model is based on the physiological processes governing mAb transport and includes two mAb-specific parameters representing differences in pinocytosis rate and the diffusive/convective transport rates among mAbs.

A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor.

Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies.

Analytical solution of linear multi-compartment models with non-zero initial condition and its implementation with R.

The analytical solution for multi-compartment models with a non-zero initial condition is complex because of the inter-compartmental transfer. An elegant solution and its implementation in the 'wnl' R package can be useful in solving examples of textbooks and developing software of therapeutic drug monitoring, pharmacokinetic simulation, and parameter estimation. This solution uses Laplace transformation, convolution, matrix inversion, and the fact that the general solution of an inhomogeneous ordinary differential equation is the sum of a homogenous and a particular solution, together.

Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis.

Over the past decade, the prevalence of infections involving methicillin-resistant (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis.

Acute pulmonary exacerbations (APE) involving are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent activity against isolates recovered from CF patients, including drug-resistant strains.

RAD-ADAPT: Software for modelling clonogenic assay data in radiation biology.

We present a comprehensive software program, RAD-ADAPT, for the quantitative analysis of clonogenic assays in radiation biology. Two commonly used models for clonogenic assay analysis, the linear-quadratic model and single-hit multi-target model, are included in the software. RAD-ADAPT uses maximum likelihood estimation method to obtain parameter estimates with the assumption that cell colony count data follow a Poisson distribution.

Population-based meta-analysis of roxithromycin pharmacokinetics: dosing implications of saturable absorption and protein binding.

Objectives: The macrolide antibiotic roxithromycin has seen widespread clinical use for several decades; however, no population pharmacokinetic analysis has been published. Early studies indicated saturation of protein binding and absorption at doses within the approved range, which may impact pharmacodynamic target attainment since regimens of 150 mg twice daily and 300 mg once daily are used interchangeably in clinical practice. This study aimed to develop a population-based meta-analysis of roxithromycin pharmacokinetics, and utilize this model to inform optimal dosing regimens.

Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice.

Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice.