Flux-Based Formulation Development —A Proof of Concept Study
AbstractThe work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipien...
Source: The AAPS Journal - January 5, 2022 Category: Drugs & Pharmacology Source Type: research
Evaluation of Excipient Risk in BCS Class I and III Biowaivers
The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have establishedin vivo bioequivalence standards and, as a result, may waive thein vivo requirement, known as a biowaiver, for some ...
Source: The AAPS Journal - January 5, 2022 Category: Drugs & Pharmacology Source Type: research
Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling
AbstractThe present work aimed to differentiate betweenin vitro dissolution profiles of ibuprofen as input for GastroPlus ™ and to see the impact on systemic exposure.In vitro dissolution profiles of ibuprofen obtained under low- and high-buffered dissolution media were used as input using the z-factor approach. In a second step, a customized surface pH calculator was applied to predict the surface pH of ibuprofen under these low- and high-buffered dissolution conditions. These surface pH values were adopted in GastroPlus ™ and simulations were performed to predict the systemic outcome. Simulated data were compared wit...
Source: The AAPS Journal - January 4, 2022 Category: Drugs & Pharmacology Source Type: research
Machine Learning and Artificial Intelligence in Pharmaceutical Research and Development: a Review
AbstractOver the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automat...
Source: The AAPS Journal - January 4, 2022 Category: Drugs & Pharmacology Source Type: research
Zwitterionic Polymer Coatings Enhance Gold Nanoparticle Stability and Uptake in Various Biological Environments
AbstractZwitterionic polymers are a class of materials that have demonstrated utility as non-fouling surfaces for medical devices and drug delivery vehicles. Here, we develop a synthesis protocol to produce zwitterionic polymers as coatings for gold nanoparticles and evaluate nanoparticle stability and biological function after exposure to various biological fluids. Thiol-functionalized polymethacryloyloxyethyl phosphorylcholine polymers (pMPC) were synthesized in nontoxic solvents via photoinitiated free radical polymerization with a radical addition-fragmentation chain transfer (RAFT) agent and coated onto gold nanoparti...
Source: The AAPS Journal - January 4, 2022 Category: Drugs & Pharmacology Source Type: research
Exploring the Relationship of Drug BCS Classification, Food Effect, and Gastric pH-Dependent Drug Interactions
AbstractFood effect (FE) and gastric pH-dependent drug-drug interactions (DDIs) are both absorption-related. Here, we evaluated if Biopharmaceutics Classification System (BCS) classes may be correlated with FE or pH-dependent DDIs. Trends in FE data were investigated for 170 drugs with clinical FE studies from the literature and new drugs approved from 2013 to 2019 by US Food and Drug Administration. A subset of 38 drugs was also evaluated to determine whether FE results can inform the need for a gastric pH-dependent DDI study. The results of FE studies were defined as no effect (AUC ratio 0.80 –1.25), increased exposure...
Source: The AAPS Journal - December 27, 2021 Category: Drugs & Pharmacology Source Type: research
Assessment of Functional Characterization and Comparability of Biotherapeutics: a Review
AbstractAbstract. The development of monoclonal antibody (mAb) biosimilars is a complex process. The key to their successful development and commercialization is an in-depth understanding of the key product attributes that impact safety and efficacy and the strategies to control them. Functional assessment of mAb is a crucial part of the comparability of biopharmaceutical drugs. The development of a relevant and robust functional assay requires an interdisciplinary approach and sufficient flexibility to balance regulatory concerns as well as dynamics and variability during the manufacturing process. Although many advanced ...
Source: The AAPS Journal - December 20, 2021 Category: Drugs & Pharmacology Source Type: research
Reactive Oxygen Species –Responsive Celastrol-Loaded Bilirubin Nanoparticles for the Treatment of Rheumatoid Arthritis
AbstractCelastrol (CLT) has shown anti-rheumatic activity against rheumatoid arthritis, while its poor water solubility and high organ toxicity restrict its further therapeutic applications. To mitigate these challenges, a reactive oxygen species (ROS) –responsive nanoparticle was developed for celastrol delivery based on the excessive ROS at the pathologic sites, which was synthesized by conjugating bilirubin to a polyethylene glycol (PEG) chain. The PEGylated bilirubin self-assembled into nanoparticle (BRNP) in aqueous solution had a hydrodyna mic diameter of around 68.6 nm, and celastrol was loaded into BRNP (CLT/BRN...
Source: The AAPS Journal - December 14, 2021 Category: Drugs & Pharmacology Source Type: research
Reactive Oxygen Species –Responsive Celastrol-Loaded
AbstractCelastrol (CLT) has shown anti-rheumatic activity against rheumatoid arthritis, while its poor water solubility and high organ toxicity restrict its further therapeutic applications. To mitigate these challenges, a reactive oxygen species (ROS) –responsive nanoparticle was developed for celastrol delivery based on the excessive ROS at the pathologic sites, which was synthesized by conjugating bilirubin to a polyethylene glycol (PEG) chain. The PEGylated bilirubin self-assembled into nanoparticle (BRNP) in aqueous solution had a hydrodyna mic diameter of around 68.6 nm, and celastrol was loaded into BRNP (CLT/BRN...
Source: The AAPS Journal - December 14, 2021 Category: Drugs & Pharmacology Source Type: research
PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake
AbstractDosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of such patients from pivotal clinical trials. Physiologically based pharmacokinetic (PBPK) modelling supports model-informed dosing when clinical data are lacking, but application of these approaches to patients with impaired renal function is not yet at full maturity. In the current study, a ganciclovir PBPK model was developed for patients with normal renal function and extended to CKD population. CKD-related changes in tubular secretion were explored in the mechanistic kidney model and implemented either as proportional or non-pr...
Source: The AAPS Journal - December 14, 2021 Category: Drugs & Pharmacology Source Type: research
Efficacy and Safety Exposure –Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma
AbstractWe developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure –response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 stu dies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepi...
Source: The AAPS Journal - December 10, 2021 Category: Drugs & Pharmacology Source Type: research
Comparison of Predictions by BCS, rDCS and Machine Learning for the Effect of Food on Oral Drug Absorption Based on Features Calculated In silico
In this study, observed food effects of 473 drugs were categorized into positive, negative, or no effects and compared with the predictions made by machine learning (ML), the Biopharmaceutics Classification System (BCS) and refined Developability Classification System (rDCS). All methods used primarily in silico estimates for prediction, and for ML, four algorithms were evaluated using nested cross-validation to select important information from 371 features calculated based on the chemical structure. Approximately 18 features, including estimated solubility in biorelevant media, were selected as important, and the random ...
Source: The AAPS Journal - December 10, 2021 Category: Drugs & Pharmacology Source Type: research
Predicting the Drug –Drug Interaction Mediated by CYP3A4 Inhibition: Method Development and Performance Evaluation
AbstractThe prediction of drug –drug interactions (DDIs) plays critical roles for the estimation of DDI risk caused by inhibition of CYP3A4. The aim of this paper is to develop a physiologically based pharmacokinetic (PBPK)-DDI model for prediction of the DDI co-administrated with ketoconazole in humans and evaluate the predict ive performance of the model. The pharmacokinetic and biopharmaceutical properties of 35 approved drugs, as victims, were collected for the development of a PBPK model, which were linked to the PBPK model of ketoconazole for the DDI prediction. The PBPK model of victims and ketoconazole were valid...
Source: The AAPS Journal - December 10, 2021 Category: Drugs & Pharmacology Source Type: research
Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers
AbstractThe therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X50) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (D...
Source: The AAPS Journal - December 7, 2021 Category: Drugs & Pharmacology Source Type: research
Development of Lipidoid Nanoparticles for siRNA Delivery to Neural Cells
AbstractLipidoid nanoparticles (LNPs) are the delivery platform in Onpattro, the first FDA-approved siRNA drug. LNPs are also the carriers in the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines. While these applications have demonstrated that LNPs effectively deliver nucleic acids to hepatic and muscle cells, it is unclear if LNPs could be used for delivery of siRNA to neural cells, which are notoriously challenging delivery targets. Therefore, the purpose of this study was to determine if LNPs could efficiently deliver siRNA to neurons. Because of their potential delivery utility in either applications for the centra...
Source: The AAPS Journal - December 6, 2021 Category: Drugs & Pharmacology Source Type: research
