Population Pharmacokinetics (PopPK) Support for Pediatric Dosing of Biological Products.

This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed.

Clinical Pharmacology of Glucagon.

Glucagon was discovered about a hundred years ago and its role in health and disease is under continuous investigation. Glucagon is a counter regulatory hormone secreted by alpha cells of the pancreas in response to multiple stimuli. Although some of glucagon's actions and its clinical application have been described, clinical experience with glucagon has been historically overshadowed by that of insulin.

Inclusion of Subjects who are Obese in Drug Development: Current Status and Opportunities.

The prevalence of obesity has grown tremendously in recent years and this population has an increased risk of disease comorbidities. The presence of disease comorbidities requires treatment interventions and proper dosing guidelines. However, drug development programs often do not have adequate representation of individuals who are obese in clinical trials, leaving gaps in the understanding of treatment response leading to a lack of adequate individualization options.

Need for Representation of Pediatric Patients with Obesity in Clinical Trials.

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products.

Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report.

The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions.

Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation.

Theoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2-3 h only; and (2) the percentage of drug release from an ER product within the first 2-3 h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestinal transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absorption of ER drugs under fed state occurs in both small and large intestines.

Leveraging Clinical Pharmacology Data to Assess Biosimilarity and Interchangeability of Insulin Products.

There is over a hundred years of clinical experience with insulin for the treatment of diabetes. The US Food and Drug Administration (FDA) approved the first insulin biosimilar interchangeable product in 2021 for improving glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Several recombinant insulin products are available in the United States, including the recently approved biosimilar insulins.

Efficacy of deep brain stimulation of the anterior-medial globus pallidus internus in tic and non-tic related symptomatology in refractory Tourette syndrome.

Introduction: Although refractory Tourette Syndrome (TS) is rare, it poses great challenges in clinical practice. Co-morbid psychiatric symptoms often occur, negatively impacting quality of life. Deep brain stimulation (DBS) targeting different brain structures seems effective for tics, but specific literature regarding response of psychiatric symptoms is more limited.

Pediatric Drug Development Studies for Familial Hypercholesterolemia Submitted to the US Food and Drug Administration Between 2007 and 2020.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism that leads to an increased risk of developing atherosclerosis and coronary artery disease. Hypercholesterolemia in pediatric patients is typically due to FH. Treatment of pediatric FH is achieved through lifestyle modifications, lipid-modifying pharmacotherapy, and/or apheresis.

Coexistence of deep brain stimulators and cardiac implantable electronic devices: A systematic review of safety.

As the number of patients implanted with deep brain stimulation systems increases, coexistence with cardiac implantable electronic devices (CIEDs) poses questions about safety. We systematically reviewed the literature on coexisting DBS and CIED. Eighteen reports of 34 patients were included.

Using Preimplanted Deep Brain Stimulation Electrodes for Rescue Thalamotomy in a Case of Holmes Tremor: A Case Report and Review of the Literature.

Background: Chronic stimulation of the thalamus is a surgical option in the management of intractable Holmes tremor. Patients with deep brain stimulation (DBS) can encounter infection as a postoperative complication, necessitating explantation of the hardware. Some studies have reported on the technique and the resulting efficacy of therapeutic lesioning through implanted DBS leads before their explantation.

Results of the 2018 Rapid DNA Maturity Assessment.

Three commercially available integrated rapid DNA instruments were tested as a part of a rapid DNA maturity assessment in July of 2018. The assessment was conducted with sets of blinded single-source reference samples provided to participants for testing on the individual rapid platforms within their laboratories. The data were returned to the National Institute of Standards and Technology (NIST) for review and analysis.

Developmental validation of the ANDE™ rapid DNA system with FlexPlex™ assay for arrestee and reference buccal swab processing and database searching.

A developmental validation was performed to demonstrate reliability, reproducibility and robustness of the ANDE System with the FlexPlex assay, including an integrated Expert System, across a number of laboratories and buccal sample variations. Previously, the related DNAscan™/ANDE 4C Rapid DNA System using the PowerPlex16 assay and integrated Expert System Software received NDIS approval in March 2016. The enhanced ANDE instrument, referred to as ANDE 6C, and the accompanying 6-dye, 27-locus STR assay, referred to as FlexPlex, have been developed to be compatible with all widely used global loci, including the expanded set of the CODIS core 20 loci.

Longitudinal neuropsychological outcomes in treatment-resistant depression following bed nucleus of the stria terminalis-area deep brain stimulation: a case review.

Studies have demonstrated the effectiveness of deep brain stimulation (DBS) as a treatment modality for psychiatric conditions. We present a case reviewing the longitudinal neuropsychological performance outcomes following bed nucleus of the stria terminalis-area (BNST) DBS in a patient with treatment-resistant depression (TRD). The cognitive safety of DBS is well documented for various targets, however cognitive outcomes of BNST-area DBS have not been extensively reported for patients with TRD.

Initial Results of Bilateral Subthalamic Nucleus Stimulation for Parkinson Disease in a Newly Established Center in a Developing Country: Shiraz, Southern Iran.

Objective: To report the establishment of a new center for deep brain stimulation (DBS) as a surgical treatment for Parkinson disease and the surgical outcomes, from 2014 to 2017 in Shiraz, Southern Iran.

Methods: A new treatment program was established in Shiraz through a multidisciplinary team in 2014. Thirty-four patients underwent implantation of subthalamic nucleus (STN) electrodes during the last 3 years.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided.

Elastic, viscoelastic and viscoplastic contributions to compliance during deformation under stress in prosthodontic temporization materials.

The goal of this investigation was to characterize the compliance properties in selected polymers used for temporary (provisional crown and bridge) applications. Polymethyl methacrylate (PMMA)- and polyethyl methacrylate (PEMA)-based JET and TRIM II were investigated along with two bisacryl composite resins (LUXATEMP and PROTEMP 3 GARANT). Rectangular samples of the resins were subjected to creep-recovery tests in a dynamic mechanical analyzer at and near the oral temperature (27 °C, 37 °C and 47 °C).

Study of visible light activated polymerization in BisGMA-TEGDMA monomers with Type 1 and Type 2 photoinitiators using Raman spectroscopy.

Objective: The goal of the study was to characterize the efficiency of polymerization of Type 1 and Type 2 initiators for visible light cure of a BisGMA-TEGDMA monomer mixture.

Methods: Raman spectroscopy was used to follow conversion during polymerization of a BisGMA-TEGDMA mixture using a Type I photoinitiator diphenyl(2,4,6 dimethylbenzoyl)phosphine oxide (TPO) and a Type II photoinitiator camphorquinone (CQ) and an amine, both initiators at 0.5wt.

Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1.

Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50 , fu,p ) and in vivo (eg, dose, Cmax , change in area under the curve [AUC]) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies.

Spatial distance between anatomically- and physiologically-identified targets in subthalamic nucleus deep brain stimulation in Parkinson's disease.

Background: Subthalamic nucleus (STN) stimulation is the treatment of choice for carefully chosen patients with idiopathic Parkinson's disease (PD) and refractory motor fluctuations. We evaluated the value of intraoperative electrophysiology during STN deep brain stimulation (DBS) procedures in refining the anatomically-defined target.

Methods: We determined the spatial distance between the anatomical and physiological targets along x, y and z axes in 50 patients with PD who underwent bilateral subthalamic nucleus DBS surgery.

Visible light cure characteristics of a cycloaliphatic polyester dimethacrylate alternative oligomer to bisGMA.

: The goal of this study was to characterize the light curing characteristics of a new oligomer PEM-665 designed to be used as an alternative monomer to BisGMA. : PEM-665 (P) and BisGMA (B) solutions were prepared with triethylene glycol dimethacrylate (T) diluent in different weight proportions (70/30 and 50/50). Solutions containing 70% P and 30% T were designated as 70PT, 70%B and 30%T as 70BT, 50%P and 50%T as 50PT and 50%B and 50%T as 50BT.

Kidney function changes with aging in adults: comparison between cross-sectional and longitudinal data analyses in renal function assessment.

The study evaluated whether the renal function decline rate per year with age in adults varies based on two primary statistical analyses: cross-section (CS), using one observation per subject, and longitudinal (LT), using multiple observations per subject over time. A total of 16628 records (3946 subjects; age range 30-92 years) of creatinine clearance and relevant demographic data were used. On average, four samples per subject were collected for up to 2364 days (mean: 793 days).

Validity of predictive models of stress relaxation in selected dental polymers.

Objective: The goal of this investigation was to assess validity of predictive models of stress relaxation in dental polymers when applied to extended master curves generated from short time experimental data by WLF time temperature superposition method.

Methods: The stress relaxation modulus changes with time at three different temperatures near the ambient body temperature were determined for selected mono-methacrylate (PEMA and PMMA) and dimethacrylate (bis-acryl) dental polymers. WLF time-temperature superposition procedure of logarithmic shift of the data from other temperatures to those at 37°C was used to generate extended master curves of relaxation modulus changes with time.

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization.

Canagliflozin (INVOKANA™) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions).

Analysis of stress relaxation in temporization materials in dentistry.

Objective: Although temporization is intended as an interim step, complexity of individual treatment situations may demand medium to longer term use of temporary appliances in clinical practice. The durability and integrity of these restorations for continued use to meet the treatment demands is therefore an important clinical problem. The goal of this study was to evaluate the short to medium term stability of these materials under controlled loading to study their stress relaxation behavior.