Real-Time Tracking of In Situ-Forming Alginate Hydrogel by Contrast-Enhanced Computed Tomography
AbstractHydrogel-based biomaterials have gained broad acceptance for tissue engineering and drug delivery applications. As their function generally depends on their localization, identifying the hydrogel position in the body is relevant and will alert physicians about potentially dangerous hydrogel migration. Monitoring the localization of hydrogels by imaging is challenging due to their high water content. Here, we developed a method to render alginate hydrogels visible on computed tomography (CT) and X-ray for real-time tracking of hydrogels inside the body. This method is based on physically immobilizing emulsion drople...
Source: The AAPS Journal - August 8, 2023 Category: Drugs & Pharmacology Source Type: research
PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper
AbstractInterest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are gener...
Source: The AAPS Journal - July 31, 2023 Category: Drugs & Pharmacology Source Type: research
Stochastic Differential Equation-based Mixed Effects Model of the Fluid Volume in the Fasted Stomach in Healthy Adult Human
AbstractThe rate and extent of drug dissolution and absorption from a solid oral dosage form depend largely on the fluid volume along the gastrointestinal tract. Hence, a model built upon the gastric fluid volume profiles can help to predict drug dissolution and subsequent absorption. To capture the great inter- and intra-individual variability (IAV) of the gastric fluid volume in fasted human, a stochastic differential equation (SDE)-based mixed effects model was developed and compared with the ordinary differential equation (ODE)-based model. Twelve fasted healthy adult subjects were enrolled and had their gastric fluid ...
Source: The AAPS Journal - July 27, 2023 Category: Drugs & Pharmacology Source Type: research
Biopharmaceutics Risk Assessment —Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions
AbstractQuality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impactin vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors....
Source: The AAPS Journal - July 27, 2023 Category: Drugs & Pharmacology Source Type: research
Real-World Evidence of the Top 100 Prescribed Drugs in the USA and Their Potential for Drug Interactions with Nirmatrelvir; Ritonavir
AbstractNirmatrelvir (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 drug-metabolizing enzymes and transporters, including cytochrome P450 (CYP) 3A, CYP2D6, and P-glycoprotein transporters. To better understand the extent of DDIs (or lack thereof) of nirmatrelvir; ritonavir in a clinical setting, this study u...
Source: The AAPS Journal - July 20, 2023 Category: Drugs & Pharmacology Source Type: research
Development of a Cell-based Neutralizing Antibody Assay for Zinpentraxin Alfa: Challenges and Mitigation Strategies
AbstractTherapeutic protein drugs can potentially induce immune responses in patients and result in the production of anti-drug antibodies (ADAs), including a subset of ADAs called neutralizing antibodies (NAbs) that might cause loss of efficacy by inhibiting clinical activities of the drug. Herein, we describe the unique challenges encountered during the development of a fit-for-purpose cell-based NAb assay for a new protein modality, zinpentraxin alfa, including our strategies for assay design to overcome various matrix interferences and improve assay drug tolerance. We demonstrated that a typical biotin-drug extraction ...
Source: The AAPS Journal - July 20, 2023 Category: Drugs & Pharmacology Source Type: research
Comparison of Analytical Procedures in Method Transfer and Bridging Experiments
AbstractComparison of two analytical procedures is the primary objective of a method transfer or when replacing an old procedure with a new one in a single lab. Guidance for comparing two analytical procedures is provided in USP<1010> based on separate tests for accuracy and precision. Determination of criteria is somewhat problematic for these comparisons because of the interdependence of accuracy and precision. In this paper, a total error approach is proposed that requires a single criterion based on an allowable out-of-specification (OOS) rate at the receiving lab. This approach overcomes the difficulty of alloca...
Source: The AAPS Journal - July 20, 2023 Category: Drugs & Pharmacology Source Type: research
Robust and Adaptive Two-stage Designs in Nonlinear Mixed Effect Models
AbstractTo get informative studies for nonlinear mixed effect models (NLMEM), design optimization can be performed based on Fisher Information Matrix (FIM) using the D-criterion. Its computation requires knowledge about models and parameters, which are often prior guesses. Thus, adaptive designs composed of several stages may be used. Robust approach can also be used to account for various candidate models. In the estimation step of a given stage, model selection (MS) or model averaging (MA) can be performed. In this work we propose a new two-stage adaptive design strategy, based on the robust expected FIM and MA over seve...
Source: The AAPS Journal - July 13, 2023 Category: Drugs & Pharmacology Source Type: research
Glucose-Responsive Microgel Comprising Conventional Insulin and Curcumin-Laden Nanoparticles: a Potential Combination for Diabetes Management
AbstractSuccessful management of type 2 diabetes mellitus (T2DM), a complex and chronic disease, requires a combination of anti-hyperglycemic and anti-inflammatory agents. Here, we have conceptualized and tested an integrated “closed-loop mimic” in the form of a glucose-responsive microgel (GRM) based on chitosan, comprising conventional insulin (INS) and curcumin-laden nanoparticles (nCUR) as a potential strategy for effective management of the disease. In addition to mimicking the normal, on-demand INS secretion, s uch delivery systems display an uninterrupted release of nCUR to combat the inflammation, oxidative str...
Source: The AAPS Journal - July 13, 2023 Category: Drugs & Pharmacology Source Type: research
An AI Approach to Generating MIDD Assets Across the Drug Development Continuum
AbstractModel-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 types provide a more holistic view of disease biology and potentially disease progression depending on the appropriateness of the underlying data sources for that purpose. Despite this awareness, most data integration and model development a...
Source: The AAPS Journal - July 10, 2023 Category: Drugs & Pharmacology Source Type: research
Neutralizing Antibody Validation Testing and Reporting Harmonization
AbstractEvolving 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 industry and the Food and Drug Administration addressed challenges unique to cell-based and non-cell-based neutralizing antibody assays. Harmonization of validation expectations and data reporting will facilitate filings to health authorities...
Source: The AAPS Journal - July 8, 2023 Category: Drugs & Pharmacology Source Type: research
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 found that CBZ dissolution was poorly sensitive to cha nges in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 μM (Ad-FaSSIFvs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolutio...
Source: The AAPS Journal - June 29, 2023 Category: Drugs & Pharmacology Source Type: research
Enhanced Pharmacokinetic Bioanalysis of Antibody –drug Conjugates using Hybrid Immunoaffinity Capture and Microflow LC-MS/MS
This study aimed to evaluate the feasibility of a hybrid immunoaffinity (IA) capture microflow LC–MS/MS (μLC-MS/MS) method for ADC analysis, utilizin g a minimal sample volume for PK assessments in a preclinical study. A robust workflow was established for the quantitative analysis of ADCs by the implementation of solid-phase extraction (SPE) and semi-automation in µLC-MS/MS. Utilizing the µLC-MS/MS approach in conjunction with 1 µL of ADC-dos ed mouse plasma sample volume, standard curves of two representative surrogate peptides for total antibody (heavy chain, HC) and intact antibody (light chain, LC) ranged from 1...
Source: The AAPS Journal - June 29, 2023 Category: Drugs & Pharmacology Source Type: research
A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models
AbstractCapturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Expos...
Source: The AAPS Journal - June 28, 2023 Category: Drugs & Pharmacology Source Type: research
Lipid Nanoparticle-Enabled Intracellular Delivery of Prime Editors
AbstractPrime editing is an advanced gene editing platform with potential to correct almost any disease-causing mutation. As genome editors have evolved, their size and complexity have increased, hindering delivery technologies with low-carrying capacity and endosomal escape. We formulated an array of lipid nanoparticles (LNPs) containing prime editors (PEs). We were able to encapsulate PEs in LNPs and confirmed the presence of PE mRNA and two different guide RNAs using HPLC. In addition, we developed a novel reporter cell line for rapid identification of LNPs suited for prime editing. A 54% prime editing rate was observed...
Source: The AAPS Journal - June 28, 2023 Category: Drugs & Pharmacology Source Type: research
