The AAPS Journal

https://link.springer.com/journal/12248

List of Papers (Total 442)

Novel Selective Quantification of Zinpentraxin Alfa Biotherapeutic in the Presence of Endogenous Isomer in Plasma Samples of Idiopathic Pulmonary Fibrosis Patients Using Immunoaffinity LC–MS

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease that affects three million patients worldwide and currently without an effective cure. Zinpentraxin alfa, a recombinant human pentraxin-2 (rhPTX-2) protein, has been evaluated as a potential drug candidate for the treatment of IPF. Clinical pharmacokinetic analysis of zinpentraxin alfa has been...

Pharmacodynamics of Cyclin D1 Degradation in Ovarian Cancer Xenografts with Repeated Oral SHetA2 Dosing

SHetA2 is a promising, orally active small molecule with anticancer properties that target heat shock proteins. In this study, we aimed to investigate the pharmacodynamic (PD) effects of SHetA2 using preclinical in vitro and in vivo models of ovarian cancer and establish a physiologically based pharmacokinetic (PBPK)/PD model to describe their relationships with SHetA2...

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates...

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS...

Drug Dissolution in Oral Drug Absorption: Workshop Report

The in-person workshop “Drug Dissolution in Oral Drug Absorption” was held on May 23–24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics...

A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications

A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during...

Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development

Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug’s behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of...

Single Particle Chemical Characterisation of Nanoformulations for Cargo Delivery

Nanoparticles can encapsulate a range of therapeutics, from small molecule drugs to sensitive biologics, to significantly improve their biodistribution and biostability. Whilst the regulatory approval of several of these nanoformulations has proven their translatability, there remain several hurdles to the translation of future nanoformulations, leading to a high rate of...

Addressing Domain Specificity in the Development of a Cell-Based Binding Assay for the Detection of Neutralizing Antibodies Against a CD47xPD-L1 Bispecific Antibody

PF-07257876 is a bispecific antibody being developed for the treatment of certain advanced or metastatic solid tumors. To support clinical development of PF-07257876, neutralizing antibody (NAb) assays were developed as part of a tiered immunogenicity testing approach. Because PF-07257876 targets both CD47 and PD-L1, determination of domain specificity of a NAb response may...

A Case Study for Critical Reagent Qualification for Ligand Binding Assays Using Equivalence Test Methodology

Qualifying critical reagents in ligand binding assays by parallel testing of current and candidate reagent lots is recommended by regulatory agencies and industry groups, but specific guidance on the format of reagent qualification experiments is limited. Equivalence testing is a statistically sound approach that is consistent with the objective of critical reagent qualification...

Ensemble Machine Learning Approaches Based on Molecular Descriptors and Graph Convolutional Networks for Predicting the Efflux Activities of MDR1 and BCRP Transporters

Multidrug resistance (MDR1) and breast cancer resistance protein (BCRP) play important roles in drug absorption and distribution. Computational prediction of substrates for both transporters can help reduce time in drug discovery. This study aimed to predict the efflux activity of MDR1 and BCRP using multiple machine learning approaches with molecular descriptors and graph...

Immunoinformatic Risk Assessment of Host Cell Proteins During Process Development for Biologic Therapeutics

The identification and removal of host cell proteins (HCPs) from biologic products is a critical step in drug development. Despite recent improvements to purification processes, biologics such as monoclonal antibodies, enzyme replacement therapies, and vaccines that are manufactured in a range of cell lines and purified using diverse processes may contain HCP impurities, making...

Human Brain Penetration Prediction Using Scaling Approach from Animal Machine Learning Models

Machine learning (ML) approaches have been applied to predicting drug pharmacokinetic properties. Previously, we predicted rat unbound brain-to-plasma ratio (Kpuu,brain) by ML models. In this study, we aimed to predict human Kpuu,brain through animal ML models. First, we re-evaluated ML models for rat Kpuu,brain prediction by using trendy open-source packages. We then developed...

Evolution of Antidrug Antibody Assays During the Development of Anti-Tissue Factor Pathway Inhibitor Monoclonal Antibody Marstacimab

Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic coagulation pathway. In patients with hemophilia A or B, inhibition of TFPI is an alternative therapeutic approach that augments the extrinsic coagulation pathway. Marstacimab is an investigational fully human monoclonal antibody that binds and neutralizes TFPI and is being evaluated as a...

Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (− 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their...

Real-World Evidence of the Top 100 Prescribed Drugs in the USA and Their Potential for Drug Interactions with Nirmatrelvir; Ritonavir

Nirmatrelvir (coadministered with ritonavir as PAXLOVIDTM) reduces the risk of COVID-19-related hospitalizations and all-cause death in individuals with mild-to-moderate COVID-19 at high risk of progression to severe disease. Ritonavir is coadministered as a pharmacokinetic enhancer. However, ritonavir may cause drug-drug interactions (DDIs) due to its interactions with various...

An AI Approach to Generating MIDD Assets Across the Drug Development Continuum

Model-informed drug development involves developing and applying exposure-based, biological, and statistical models derived from preclinical and clinical data sources to inform drug development and decision-making. Discrete models are generated from individual experiments resulting in a single model expression that is utilized to inform a single stage-gate decision. Other model...

Neutralizing Antibody Validation Testing and Reporting Harmonization

Evolving immunogenicity assay performance expectations and a lack of harmonized neutralizing antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. A team of experts within the American Association of Pharmaceutical Scientists’ Therapeutic Product Immunogenicity Community across...

Integration of Biorelevant Pediatric Dissolution Methodology into PBPK Modeling to Predict In Vivo Performance and Bioequivalence of Generic Drugs in Pediatric Populations: a Carbamazepine Case Study

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive...

Evaluation of the Potential for Drug-Drug Interactions with Inhaled Itraconazole Using Physiologically Based Pharmacokinetic Modelling, Based on Phase 1 Clinical Data

Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a...