Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.

Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib.

Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V.

Understanding CYP3A4 and P-gp mediated drug-drug interactions through PBPK modeling - Case example of pralsetinib.

Pralsetinib, a potent and selective inhibitor of oncogenic RET fusion and RET mutant proteins, is a substrate of the drug metabolizing enzyme CYP3A4 and a substrate of the efflux transporter P-gp based on in vitro data. Therefore, its pharmacokinetics (PKs) may be affected by co-administration of potent CYP3A4 inhibitors and inducers, P-gp inhibitors, and combined CYP3A4 and P-gp inhibitors. With the frequent overlap between CYP3A4 and P-gp substrates/inhibitors, pralsetinib is a challenging and representative example of the need to more quantitatively characterize transporter-enzyme interplay.

Treatment Trends in Pediatric Trigger Thumb Among Hand Surgeons, Pediatric Orthopedic Surgeons, and Pediatric Hand Surgeons.

Background: The appropriate initial management of pediatric trigger thumb (PTT) remains controversial. Some providers advocate for prolonged nonoperative management, whereas others may offer surgical release to provide a reliable and expedient resolution. The goal of this study was to elucidate the practice patterns of surgeons with different fellowship training who treat patients with PTT.

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

Electrocardiogram Abnormalities Following Diphenhydramine Ingestion: A Case Report.

Unlabelled: In the United States, tricyclic antidepressants (TCA) are commonly prescribed to treat psychiatric illnesses and neuropathic pain. This class of antidepressants has been found to cause pathognomonic electrocardiogram (ECG) changes in cases of overdose.1 Specifically, TCA's cause a dominant terminal R wave in aVR and widening of the QRS complex due to their sodium channel blocking effect.

Shared learning from a physiologically based pharmacokinetic modeling strategy for human pharmacokinetics prediction through retrospective analysis of Genentech compounds.

The quantitative prediction of human pharmacokinetics (PK) including the PK profile and key PK parameters are critical for early drug development decisions, successful phase I clinical trials, and the establishment of a range of doses to enable phase II clinical dose selection. Here, we describe an approach employing physiologically based pharmacokinetic (PBPK) modeling (Simcyp) to predict human PK and to validate its performance through retrospective analysis of 18 Genentech compounds for which clinical data are available. In short, physicochemical parameters and in vitro data for preclinical species were integrated using PBPK modeling to predict the in vivo PK observed in mouse, rat, dog, and cynomolgus monkey.

Evaluation of bottom-up modeling of the blood-brain barrier to improve brain penetration prediction via physiologically based pharmacokinetic modeling.

Predicting the brain penetration of drugs has been notoriously difficult; however, recently, permeability-limited brain models have been constructed. Lead optimization for central nervous system compounds often focuses on compounds that have low transporter efflux, where passive permeability could be a main driver in determining cerebrospinal fluid (CSF)/brain concentrations. The main objective of this study was to evaluate the translatability of passive permeability data generated from different in vitro systems and its impact on the prediction of human CSF/brain concentrations using physiologically-based pharmacokinetic (PBPK) modeling.

Extremity Pressure in Splints Wrapped With an Elastic Bandage Versus Bias Cut Stockinette: An Experimental Model.

Background: Many variables affect the pressure caused by splinting or casting. The purpose of this study was to compare pressure underlying a splint wrapped with either an elastic bandage or a bias cut stockinette.

Methods: Thirty-two plaster volar resting splints were applied to a simulated extremity with a saline bag secured to it.

Improving the Translation of Organic Anion Transporting Polypeptide Substrates using HEK293 Cell Data in the Presence and Absence of Human Plasma via Physiologically Based Pharmacokinetic Modeling.

Accurately predicting the pharmacokinetics of compounds that are transporter substrates has been notoriously challenging using traditional in vitro systems and physiologically based pharmacokinetic (PBPK) modeling. The objective of this study was to use PBPK modeling to understand the translational accuracy of data generated with human embryonic kidney 293 (HEK293) cells overexpressing the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1/3 with and without plasma while accounting for transporter expression. Models of four OATP substrates, two with low protein binding (pravastatin and rosuvastatin) and two with high protein binding (repaglinide and pitavastatin) were explored, and the OATP in vitro data generated in plasma incubations were used for a plasma model, and in buffer incubations for a buffer model.

Examination of Physiologically-Based Pharmacokinetic Models of Rosuvastatin.

Physiologically-based pharmacokinetic (PBPK) modeling is increasingly used to predict drug disposition and drug-drug interactions (DDIs). However, accurately predicting the pharmacokinetics of transporter substrates and transporter-mediated DDIs (tDDIs) is still challenging. Rosuvastatin is a commonly used substrate probe in DDI risk assessment for new molecular entities (NMEs) that are potential organic anion transporting polypeptide 1B or breast cancer resistance protein transporter inhibitors, and as such, several rosuvastatin PBPK models have been developed to try to predict the clinical DDI and support NME drug labeling.

Changes in Organic Anion Transporting Polypeptide Uptake in HEK293 Overexpressing Cells in the Presence and Absence of Human Plasma.

Generating accurate in vitro data is crucial for in vitro to in vivo extrapolation and pharmacokinetic predictions. The use of human embryonic kidney (HEK) 293 cells overexpressing organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 in protein-free buffer and 100% human plasma incubations was explored for the uptake of four OATP substrates: pravastatin, rosuvastatin, repaglinide, and pitavastatin. Differences were observed for each parameter [unbound Michaelis constant ( ), , intrinsic clearance (CL), and unbound passive diffusion P] obtained from the buffer and plasma incubations in both cells, and the fold differences were greatest for the highly protein bound compounds.

In Vitro-In Vivo Inaccuracy: The CYP3A4 Anomaly.

When predicting hepatic clearance using in vitro to in vivo extrapolation (IVIVE), microsomes or hepatocytes are commonly used. Here, we examine intrinsic clearance values and IVIVE results in human hepatocytes and microsomes for compounds metabolized by a variety of enzymes. The great majority of CYP3A4 substrates examined had higher intrinsic clearance values in microsomes compared with hepatocytes, whereas the values were more similar between the two incubations for substrates of other enzymes.

Use of an Accelerated Discharge Pathway in Patients With Severe Cerebral Palsy Undergoing Posterior Spinal Fusion for Neuromuscular Scoliosis.

Background: Implementation of a coordinated multidisciplinary postoperative pathway has been shown to reduce length of stay after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis. This study sought to compare the outcomes of nonambulatory cerebral palsy (CP) patients treated with PSF and cared for using an accelerated discharge (AD) pathway with those using a more traditional discharge (TD) pathway.

Methods: A total of 74 patients with Gross Motor Function Classification System (GMFCS) class 4/5 CP undergoing PSF were reviewed.

How Transporters Have Changed Basic Pharmacokinetic Understanding.

The emergence and continued evolution of the transporter field has caused re-evaluation and refinement of the original principles surrounding drug disposition. In this paper, we emphasize the impact that transporters can have on volume of distribution and how this can affect the other major pharmacokinetic parameters. When metabolic drug-drug interactions or pharmacogenomic variance changes the metabolism of a drug, the volume of distribution appears to be unchanged while clearance, bioavailability, and half-life are changed.

An Exceptionally Potent Inhibitor of Human CD73.

We recently reported the initiation of a Phase I clinical trial with AB680, a potent human CD73 inhibitor, being developed for the treatment of solid tumors (NCT03677973). We undertook a detailed kinetic analysis of the interaction between human CD73 and AB680 to determine the mode of inhibition. We found AB680 to be a reversible, slow-onset competitive inhibitor of human CD73 with a of 5 pM.

Interlaboratory Variability in Human Hepatocyte Intrinsic Clearance Values and Trends with Physicochemical Properties.

Purpose: To examine the interlaboratory variability in CL values generated with human hepatocytes and determine trends in variability and clearance prediction accuracy using physicochemical and pharmacokinetic parameters.

Methods: Data for 50 compounds from 14 papers were compiled with physicochemical and pharmacokinetic parameter values taken from various sources.

Results: Coefficients of variation were as high as 99.

Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs.

Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.

In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction.

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined.

The Presence of a Transporter-Induced Protein Binding Shift: A New Explanation for Protein-Facilitated Uptake and Improvement for In Vitro-In Vivo Extrapolation.

Accurately predicting hepatic clearance is an integral part of the drug-development process, and yet current in vitro to in vivo (IVIVE) extrapolation methods yield poor predictions, particularly for highly protein-bound transporter substrates. Explanations for error include inaccuracies in protein-binding measurements and the lack of recognition of protein-facilitated uptake, where both unbound and bound drug may be cleared, violating the principles of the widely accepted free drug theory. A new explanation for protein-facilitated uptake is proposed here, called a High-affinity binding to cell-membrane proteins may change the equilibrium of the nonspecific binding between drugs and plasma proteins, leading to greater cellular uptake and clearance than currently predicted.

A workforce in jeopardy: identifying the challenges of ensuring a sustainable advanced HIV nursing workforce.

Background: HIV services in England face substantial challenges arising from financial pressures and changes to commissioning. A sustainable HIV specialist nursing workforce will be vital to enable them to respond to those challenges.

Aims: This paper examines the current workforce situation in HIV services across the country.

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses.

Purpose: To derive the theoretical basis for the extended clearance model of organ elimination following both oral and IV dosing, and critically analyze the approaches previously taken.

Methods: We derived from first principles the theoretical basis for the extended clearance concept of organ elimination following both oral and IV dosing and critically analyzed previous approaches.

Results: We point out a number of critical characteristics that have either been misinterpreted or not clearly presented in previously published treatments.

How does specialist nursing contribute to HIV service delivery across England?

This study aimed to examine what specialist nursing contributes to HIV service delivery across England and how it could be optimised. A three part multi-method qualitative study was undertaken, involving (1) interviews with 19 stakeholders representing professional or service user groups; (2) interviews with nurse/physician pairs from 21 HIV services; and (3) case studies involving site visits to five services. A framework analysis approach was used to manage and analyse the data.

Hepatic Clearance Predictions from In Vitro-In Vivo Extrapolation and the Biopharmaceutics Drug Disposition Classification System.

Predicting in vivo pharmacokinetic parameters such as clearance from in vitro data is a crucial part of the drug-development process. There is a commonly cited trend that drugs that are highly protein-bound and are substrates for hepatic uptake transporters often yield the worst predictions. Given this information, 11 different data sets using human microsomes and hepatocytes were evaluated to search for trends in accuracy, extent of protein binding, and drug classification based on the Biopharmaceutics Drug Disposition Classification System (BDDCS), which makes predictions about transporter effects.