Pharmacokinetics, Lymph Node Uptake and Mechanistic PK Model of Near Infrared Dye Labeled Bevacizumab After IV and SC Administration in Mice

Our objective was to determine the pharmacokinetics, bioavailability and lymph node uptake of the monoclonal antibodybevacizumab, labeled with the near-infrared (IR) dye 800CW, after intravenous (IV) and subcutaneous (SC) administration inmice. Fluorescence imaging and enzyme-linked immunosorbent assay (ELISA) assays were developed and validated to measure the concentration of bevacizumab in plasma.

PEGylation of a Factor VIII-phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease.

Model-based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase … Continued

Modeling Disease Progression in Acute Stroke Using Clinical Assessment Scales

This article demonstrates techniques for describing and predicting disease progression in acute stroke by modeling scores measured using clinical assessment scales, accommodating dropout as an additional source of information. Scores assessed using the National Institutes of Health Stroke Scale and the Barthel Index in acute stroke patients were used to model the time course of … Continued

Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by … Continued

Population-based Mechanistic Prediction of Oral Drug Absorption

The bioavailability of drugs from oral formulations is influenced by many physiological factors including gastrointestinal fluid composition, pH and dynamics, transit and motility, and metabolism and transport, each of which may vary with age, gender, race, food, and disease. Therefore, oral bioavailability, particularly of poorly soluble and/or poorly permeable compounds and those that are extensively … Continued

Recent Advances in Structure-based Virtual Screening of G-protein Coupled Receptors

In addition to the rhodopsin crystal structure, high-resolution crystal structures of ligand-mediated G-protein-coupled receptors (GPCRs) have recently become available, and these have become attractive templates for developing homology models of several GPCRs of therapeutic interest. These crystal structures and the homology models derived from them have provided significant insights into ligand-receptor interactions. Moreover, several studies … Continued

In Vitro Evaluation of Reversible and Irreversible Cytochrome P450 Inhibition: Current Status on Methodologies and Their Utility for Predicting Drug-drug Interactions

It is widely accepted that today’s practice of polypharmacy inevitably increases the incidence of drug-drug interactions (DDIs). Serious DDI is a major liability for any new chemical entity (NCE) entering the pharmaceutical market. As such, pharmaceutical companies employ various strategies to avoid problematic compounds for clinical development. A key cause for DDIs is the inhibition … Continued

Model-based Development of Gemcabene, a New Lipid-altering Agent

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clinical profile of gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the cholesterol absorption inhibitor … Continued

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