Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report.

This report summarizes the proceedings for Day 3 of the workshop titled "". This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments.

Office-Based Serial Intralesional Steroid Injections in Benign Subglottic Stenosis-First Results.

Objective: Serial intralesional steroid injections (SILSI) are increasingly used in the treatment of idiopathic subglottic stenosis (iSGS) and auto-immune related subglottic stenosis (SGS), which are both known for their high rate of recurrences. SILSI could potentially prolong the time to re-intervention. We evaluated the effects of adjuvant SILSI in iSGS and auto-immune related SGS-patients on time to reintervention and spirometry results.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance.

Glottic insufficiency caused by vocal fold atrophy with or without sulcus: systematic review of outcome measurements.

Purpose: Identifying outcome measurements instruments (OMIs) to evaluate treatment efficacy in patients with vocal fold atrophy and/or sulcus.

Methods: Systematic review of records published before March 2021 by searching Pubmed and EMBASE. Included studies reported on adults (> 18 year) with dysphonia caused by glottic insufficiency due to vocal fold atrophy with or without sulcus, who were enrolled into a randomized controlled trial, a non-randomized controlled trial, a case-controlled study or a cohort study.

Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia.

Introduction: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL.

Physiologically based pharmacokinetics modeling and transporter proteomics to predict systemic and local liver and muscle disposition of statins.

Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity.

Voice outcome in medialisation thyroplasty with and without arytenoid adduction: a prospective comparison using intraoperative voice measurements.

Purpose: Arytenoid adduction as an addition to medialisation thyroplasty is highly advocated by some surgeons in selected cases but deemed less necessary by others in patients with unilateral vocal fold paralysis. This study aims to evaluate the additional benefits on voice outcome of arytenoid adduction in patients with unilateral vocal fold paralysis undergoing medialisation thyroplasty using intra-operative voice measurements.

Design/methods: A prospective study was conducted.

Quantitative imaging of doxorubicin diffusion and cellular uptake in biomimetic gels with human liver tumor cells.

Novel tumor-on-a-chip approaches are increasingly used to investigate tumor progression and potential treatment options. To improve the effect of any cancer treatment it is important to have an in depth understanding of drug diffusion, penetration through the tumor extracellular matrix and cellular uptake. In this study, we have developed a miniaturized chip where drug diffusion and cellular uptake in different hydrogel environments can be quantified at high resolution using live imaging.

Long-term outcomes of bilateral medialisation thyroplasty in patients with vocal fold atrophy with or without sulcus.

Objective: Evaluate long-term voice outcome after bilateral medialisation thyroplasty in glottic insufficiency due to vocal fold atrophy with or without sulcus.

Methods: Patients after medialisation thyroplasty for vocal fold atrophy with or without sulcus were identified. Long-term post-operative subjective voice outcomes (> 1 year) using Voice Handicap Index-30, subjective ratings on voice aspects and study-specific questionnaire were compared to pre-operative and shorter-term (1 year) values.

Consensus for voice quality assessment in clinical practice: guidelines of the European Laryngological Society and Union of the European Phoniatricians.

Introduction: To update the European guidelines for the assessment of voice quality (VQ) in clinical practice.

Methods: Nineteen laryngologists-phoniatricians of the European Laryngological Society (ELS) and the Union of the European Phoniatricians (UEP) participated to a modified Delphi process to propose statements about subjective and objective VQ assessments. Two anonymized voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 3/4.

The diagnostic accuracy of spirometry as screening tool for adult patients with a benign subglottic stenosis.

Background: There is a considerable diagnostic delay in the diagnosis 'benign acquired subglottic stenosis in adults' (SGS, diagnosed by the reference standard, i.e. laryngo- or bronchoscopy).

Pharyngeal Reconstruction Methods to Reduce the Risk of Pharyngocutaneous Fistula After Primary Total Laryngectomy: A Scoping Review.

Introduction: The most common early postoperative complication after total laryngectomy (TL) is pharyngocutaneous fistula (PCF). Rates of PCF are higher in patients who undergo salvage TL compared with primary TL. Published meta-analyses include heterogeneous studies making the conclusions difficult to interpret.

Understanding Statin-Roxadustat Drug-Drug-Disease Interaction Using Physiologically-Based Pharmacokinetic Modeling.

A different drug-drug interaction (DDI) scenario may exist in patients with chronic kidney disease (CKD) compared with healthy volunteers (HVs), depending on the interplay between drug-drug and disease (drug-drug-disease interaction (DDDI)). Physiologically-based pharmacokinetic (PBPK) modeling, in lieu of a clinical trial, is a promising tool for evaluating these complex DDDIs in patients. However, the prediction confidence of PBPK modeling in the severe CKD population is still low when nonrenal pathways are involved.

Physiologically based biopharmaceutics modeling of regional and colon absorption in humans.

Colon absorption is a key determinant for successful development of extended release and colon targeted drug products. This is the first systematic evaluation of the ability to predict in vivo regional differences in absorption and the extent of colon absorption in humans using mechanistic physiologically based biopharmaceutics modeling (PBBM). A new dataset, consisting of 19 drugs with a wide range of biopharmaceutics properties and extent of colon absorption in humans, was established.

Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates Antitumor Activity.

CD73 (ecto-5'-nucleotidase) has emerged as an attractive target for cancer immunotherapy of many cancers. CD73 catalyzes the hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive adenosine that plays a critical role in tumor progression. Herein, we report our efforts in developing orally bioavailable and highly potent small-molecule CD73 inhibitors from the reported hit molecule to lead molecule and then finally to compound .

Long-term functional outcomes in tumour stage T glottic carcinoma after radiotherapy.

Objective: To evaluate the long-term functional outcomes in patients who received primary radiotherapy for tumour-node stage TN glottic carcinoma, stratified for tumour extension.

Methods: A cross-sectional study was performed on patients who were treated with radiotherapy for TN glottic carcinoma. Four questionnaires were used to measure different aspects of functional outcome.

Does the choice of applied physiologically-based pharmacokinetics platform matter? A case study on simvastatin disposition and drug-drug interaction.

Physiologically-based pharmacokinetic (PBPK) models have an important role in drug discovery/development and decision making in regulatory submissions. This is facilitated by predefined PBPK platforms with user-friendly graphical interface, such as Simcyp and PK-Sim. However, evaluations of platform differences and the potential implications for disposition-related applications are still lacking.

Physiological based pharmacokinetic and biopharmaceutics modelling of subcutaneously administered compounds - An overview of in silico models.

Subcutaneous injection is a commonly used route of drug administration for both small molecules and biologics. To facilitate the development of new subcutaneously administered drugs, methods for prediction of drug absorption from the injection site are essential. For this purpose, in silico models have increasingly been used.

Voice Outcome After Carbon Dioxide Transoral Laser Microsurgery for Glottic Cancer According to the European Laryngological Society Classification of Cordectomy Types - A Systematic Review.

Background: Voice outcome after carbon dioxide transoral laser microsurgery (COTOLMS) for glottic cancer is of prime importance. However, a comprehensive overview according to the European Laryngological Society (ELS) classification of cordectomies is still lacking. The aim of this systematic review is to summarize data on voice outcome associated with individual types of ELS glottic cordectomy after COTOLMS.

Overview of authorized drug products for subcutaneous administration: Pharmaceutical, therapeutic, and physicochemical properties.

There is a growing body of research about subcutaneously administered biologics, emphasizing the need for optimized bioavailability predictions. It is important to inform both translational and in silico models with properties of the drug products and compounds. However, the pharmaceutical, therapeutic and physicochemical properties of market authorized drug products for subcutaneous administration are currently not collated in the public domain.

Drug diffusion in biomimetic hydrogels: importance for drug transport and delivery in non-vascular tumor tissue.

Hydrogels of varying complexity are routinely used as scaffolds and 3D structures for in vitro tumor models to increase physiological relevance within pre-clinical cancer research. Relatively simple hydrogels such as agarose are well characterised, meanwhile biomimetic gels containing collagen and fibrin(ogen) have been studied to a much lesser extent. In this study, hydrogels mimicking the biophysical characteristics of liver cancer progression were investigated in terms of their UV-properties and influence on diffusion coefficients of different substances.

Multidimensional assessment of voice quality after injection augmentation of the vocal fold with autologous adipose tissue or calcium hydroxylapatite.

Purpose: The purpose of this study was to evaluate short- and long-term outcome of injection augmentation with autologous adipose tissue (AAT) and calcium hydroxylapatite injection (CAHA) in patients with a unilateral vocal fold paralysis (UVFP).

Design/methods: A retrospective cohort study was performed in patients diagnosed with UVFP, who had received injection augmentation with AAT or CAHA. Multidimensional voice analysis was performed before, 3 and 12 months after injection.