Addressing the Accuracy of Plasma Protein Binding Measurement for Highly Bound Compounds Using the Dilution Method
In this study, the dilution method was evaluated, and the results showed that it gave similarfu values as those determined using the pre-saturation method without plasma dilution. The dilution method enables generation of accuratefu values and alignment with the regulatory recommendation of reportablefu values of ≥ 0.01 for DDI prediction. We recommend using the dilution method to bridge the regulatory recommendedfu limit of 0.01 for DDI prediction and the pre-saturation or equivalent methods for definitive plasma protein binding studies. As the pharmaceutical industry continues to generate high quality PPB data, re...
Source: The AAPS Journal - December 5, 2022 Category: Drugs & Pharmacology Source Type: research
Stability and Function of Extracellular Vesicles Derived from Immortalized Human Corneal Stromal Stem Cells: A Proof of Concept Study
AbstractWith significant advancement and development of extracellular vesicle (EV)-based therapies, there is a growing need to understand how their storage affects their physical and functional characteristics. EVs were isolated from the conditioned medium of a corneal stromal stem cell line (imCSSC) using Total Exosome isolation kit (TEI) and ultracentrifugation (UC) combined protocol. Purified EVs were stored at 4 °C, − 80°C, room temperature (RT) after lyophilization with or without trehalose for 4 weeks. EVs stored at − 80°C and RT (lyophilization with trehalose) demonstrated a comparable morphology, wh...
Source: The AAPS Journal - December 5, 2022 Category: Drugs & Pharmacology Source Type: research
End-to-End Approach to Surfactant Selection, Risk Mitigation, and Control Strategies for Protein-Based Therapeutics
AbstractA survey performed by the AAPS Drug Product Handling community revealed a general, mostly consensus, approach to the strategy for the selection of surfactant type and level for biopharmaceutical products. Discussing and building on the survey results, this article describes the common approach for surfactant selection and control strategy for protein-based therapeutics and focuses on key studies, common issues, mitigations, and rationale. Where relevant, each section is prefaced by survey responses from the 22 anonymized respondents. The article format consists of an overview of surfactant stabilization, followed b...
Source: The AAPS Journal - December 5, 2022 Category: Drugs & Pharmacology Source Type: research
Pharmacokinetics of Long-Acting Aqueous Nano-/Microsuspensions After Intramuscular Administration in Different Animal Species and Humans —a Review
AbstractFormulating aqueous suspensions is an attractive strategy to incorporate poorly water-soluble drugs, where the drug release can be tailored to maintain desired release profiles of several weeks to months after parenteral (i.e., intramuscular or subcutaneous) administration. A sustained drug release can be desirable to combat chronic diseases by overcoming pill fatigue of a daily oral intake, hence, improving patient compliance. Although the marketed aqueous suspensions for intramuscular injection efficiently relieve the daily pill burden in chronic diseases, the exact drug release mechanisms remain to be fully unra...
Source: The AAPS Journal - December 1, 2022 Category: Drugs & Pharmacology Source Type: research
Monoclonal Antibody Pharmacokinetics in Cynomolgus Monkeys Following Subcutaneous Administration: Physiologically Based Model Predictions from Physiochemical Properties
AbstractAn integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based onin silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous...
Source: The AAPS Journal - December 1, 2022 Category: Drugs & Pharmacology Source Type: research
Preclinical Observations of Systemic and Ocular Antidrug Antibody Response to Intravitreally Administered Drugs
AbstractIntravitreally administered biotherapeutics can elicit local and systemic immune responses with potentially serious clinical consequences. However, little is known about the mechanisms of ocular antidrug immune response, the incidence of ocular antidrug antibodies (ADAs), and the relationship between ocular and systemic ADA levels. Bioanalytical limitations and poor availability of ocular matrices make studies of ocular immunogenicity particularly challenging. We have recently reported a novel bioanalytical ADA assay and shown its applicability for the ADA detection in ocular matrices. In the present study, we used...
Source: The AAPS Journal - November 22, 2022 Category: Drugs & Pharmacology Source Type: research
ACUVRA: Anion-Exchange Chromatography UV-Ratio Analysis —A QC-Friendly Method for Monitoring Adeno-Associated Virus Empty Capsid Content To Support Process Development and GMP Release Testing
Abstract The genome content of adeno-associated virus (AAV) vectors is critical to the safety and potency of AAV-based gene therapy products. Empty capsids are considered a product-related impurity and a critical quality attribute (CQA) of the drug product, thus requiring characterization throughout the production process to demonstrate they are controlled to acceptable levels in the final drug product. Anion exchange chromatography has been used to achieve separation between empty and full capsids, but requires method development and gradient optimization for different serotypes and formulations. Here, we describe an al...
Source: The AAPS Journal - November 22, 2022 Category: Drugs & Pharmacology Source Type: research
A Simple One-Parameter Percent Dissolved Versus Time Dissolution Equation that Accommodates Sink and Non-sink Conditions via Drug Solubility and Dissolution Volume
AbstractIn vitro dissolution generally involves sink conditions, so dissolution equations generally do not need to accommodate non-sink conditions. Greater use of biorelevant media, which are typically less able to provide sink conditions than pharmaceutical surfactants, necessitates equations that accommodate non-sink conditions. One objective was to derive an integrated, one-parameter dissolution equation for percent dissolvedversus time that accommodates non-sink effectsvia drug solubility and dissolution volume parameters, including incomplete solubility. A second objective was to characterize the novel equation by fit...
Source: The AAPS Journal - November 17, 2022 Category: Drugs & Pharmacology Source Type: research
Individualized Patient Care Through Model-Informed Precision Dosing: Reflections on Training Future Practitioners
AbstractPrior to his passing, Dr. Roger Jelliffe, expressed the need for educating future physicians and clinical pharmacists on the availability of computer-based tools to support dose optimization in patients in stable or unstable physiological states. His perspectives were to be captured in a commentary for the AAPS J with a focus on incorporating population pharmacokinetic (PK)/pharmacodynamic (PD) models that are designed to hit the therapeutic target with maximal precision. Unfortunately, knowing that he would be unable to complete this project, Dr. Jelliffe requested that a manuscript conveying his concerns be compl...
Source: The AAPS Journal - November 15, 2022 Category: Drugs & Pharmacology Source Type: research
A Non-radiometric Approach to Determine Tissue Vascular Blood Volume in Biodistribution Studies
AbstractThe aim of this research was to develop a reliable non-radiometric method to measure the residual blood in tissue without the need for perfusion or radiometric measurements in biodistribution studies. It was found that the perfusion method not only was ineffective in removing blood from tissue, but also introduced additional variability in the determination of tissue drug exposure and was not reproducible across studies. In addition, the use of hemoglobin as an endogenous protein and biomarker for tissue blood content was studied and it was found that hemoglobin measurement in tissue was not a reliable and effectiv...
Source: The AAPS Journal - November 14, 2022 Category: Drugs & Pharmacology Source Type: research
Determination of Anti-drug Antibody Affinity in Clinical Study Samples Provides a Tool for Evaluation of Immune Response Maturation
AbstractCharacterization of clinical anti-drug antibody (ADA) responses to biotherapeutics can be important to understanding the consequences of immunogenicity. ADA are expected to be polyclonal, with composition and affinities that evolve over time. Measuring ADA binding affinity can be complicated by the polyclonal nature of response, residual drug in sample, and low ADA levels. We developed a novel workflow to determine the apparent ADA affinity (KD) against a monoclonal antibody biotherapeutic, PF-06480605. An affinity capture elution pre-treatment step was used to isolate ADA and remove residual drug interference from...
Source: The AAPS Journal - November 2, 2022 Category: Drugs & Pharmacology Source Type: research
DNA Methylome and Transcriptome Study of Triterpenoid CDDO in TPA-Mediated Skin Carcinogenesis Model
This study investigated the methylome and transcriptome altered by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or TPA with 2-cyano 2,3-dioxoolean-1,9-dien-28-oic acid (CDDO). The results show that CDDO blocks TPA-induced transformation dose dependently. Several differential expressed genes (DEGs) involved in skin cell transformation, while counteracted by CDDO, were revealed by differential expression analysis includingLyl1,Lad1, andDennd2d. In CpG methylomic profiles, the differentially methylated regions (DMRs) in the promoter region altered by TPA while showing the opposite methylation status in the CDDO t...
Source: The AAPS Journal - November 2, 2022 Category: Drugs & Pharmacology Source Type: research
Anti-drug Antibody Sample Testing and Reporting Harmonization
AbstractA clear scientific and operational need exists for harmonized bioanalytical immunogenicity study reporting to facilitate communication of immunogenicity findings and expedient review by industry and health authorities. To address these key bioanalytical reporting gaps and provide a report structure for documenting immunogenicity results, this cross-industry group was formed to establish harmonized recommendations and a develop a submission template to facilitate agency filings. Provided here are recommendations for reporting clinical anti-drug antibody (ADA) assay results using ligand-binding assay technologies. Th...
Source: The AAPS Journal - October 28, 2022 Category: Drugs & Pharmacology Source Type: research
A Novel Bootstrapping Test for Analytical Biosimilarity
AbstractShowing analytical similarity is key to license biosimilar products with reduced or circumvented clinical effort. Statistical procedures to assess analytical similarity of quality attributes at drug product level have been highly debated by academia, industry, and regulatory agencies. In the past, a tiered approach was recommended by regulators, consisting of equivalence tests and quality range tests. However, this approach has recently been withdrawn by FDA. New guidelines of FDA and EMA favour the usage of quality range tests. Moreover, it has recently been shown that simple range tests, such as the 3SD test, are...
Source: The AAPS Journal - October 21, 2022 Category: Drugs & Pharmacology Source Type: research
Risk Factors, Hyaluronidase Expression, and Clinical Immunogenicity of Recombinant Human Hyaluronidase PH20, an Enzyme Enabling Subcutaneous Drug Administration
AbstractMultiple FDA-approved and clinical-development stage therapeutics include recombinant human hyaluronidase PH20 (rHuPH20) to facilitate subcutaneous administration. As rHuPH20-reactive antibodies potentially interact with endogenous PH20, we investigated rHuPH20 immunogenicity risk through hyaluronidase tissue expression, predicted B cell epitopes, CD4+ T cell stimulation indices and related these to observed clinical immunogenicity profiles from 18 clinical studies. Endogenous hyaluronidase PH20 expression in humans/mice was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative RT-PCR, ...
Source: The AAPS Journal - October 20, 2022 Category: Drugs & Pharmacology Source Type: research
