Benchmarking the Quality Practices of Global Pharmaceutical Manufacturing to Advance Supply Chain Resilience
AbstractOver the past several decades, pharmaceutical manufacturing has become increasingly global and supply chains have become longer, more complex, and fragmented. While pharmaceutical products available to patients and customers typically conform with appropriate standards, supply chains are often affected by disruptive events and shocks that impact public health. One approach to assuring the availability of quality pharmaceutical products is to encourage drug manufacturers to invest in quality management maturity (QMM) and promote continual improvement. The interests of patients are served by risk-based drug shortage ...
Source: The AAPS Journal - October 20, 2022 Category: Drugs & Pharmacology Source Type: research
Identification of Potential Megalin/Cubilin Substrates Using Extensive Proteomics Quantification from Kidney Megalin-Knockdown Mice
In conclusion, analysis of urine samples from kidney-specific megalin KD and WT mice was found to be useful for the identification of potential endogenous substrates for megalin and cubilin.Graphical Abstract (Source: The AAPS Journal)
Source: The AAPS Journal - October 17, 2022 Category: Drugs & Pharmacology Source Type: research
FOLFIRINOX Pharmacodynamic Interactions in 2D and 3D Pancreatic Cancer Cell Cultures
AbstractThe multi-drug combination regime, FOLFIRINOX, is a standard of care chemotherapeutic therapy for pancreatic cancer patients. However, systematic evaluation of potential pharmacodynamic interactions among multi-drug therapy has not been reported previously. Here, pharmacodynamic interactions of the FOLFIRINOX agents (5-fluorouracil (5-FU), oxaliplatin (Oxa) and SN-38, the active metabolite of irinotecan) were assessed across a panel of primary and established pancreatic cancer cells. Inhibition of cell proliferation was quantified for each drug, alone and in combination, to obtain quantitative, drug-specific intera...
Source: The AAPS Journal - October 13, 2022 Category: Drugs & Pharmacology Source Type: research
Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1
AbstractTYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also...
Source: The AAPS Journal - October 7, 2022 Category: Drugs & Pharmacology Source Type: research
Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody
Abstract
The development of new antibody –drug conjugates (ADCs) has led to the approval of 7 ADCs by the FDA in 4 years. Given the impact of intratumoral distribution on efficacy of these therapeutics, coadministration of unconjugated antibody with ADC has been shown to improve distribution and efficacy of several ADCs in high and mode rately expressed tumor target systems by increasing tissue penetration. However, the benefit of coadministration in low expression systems is less clear. TAK-164, an ADC composed of an anti-GCC antibody (5F9) conjugated to a DGN549 payload, has demonstrated heterogeneous distribution ...
Source: The AAPS Journal - October 7, 2022 Category: Drugs & Pharmacology Source Type: research
Does an Intradermal Vaccination for Monkeypox Make Sense?
AbstractMankind has recently had to deal a series of virus-mediated pandemics, resulting in extensive morbidity and mortality rates that have severely strained healthcare systems. While dealing with viral infections as a healthcare concern is not new, our exceptionally mobile society has added to the critical challenge of limiting pathogen spread of a highly transmissible virus prior to the generation, testing, and distribution of safe and effective vaccines. The tremendous global effort put forth to address the recent pandemic induced by SARS-CoV-2 infection has highlighted many of the strengths and weaknesses of how vacc...
Source: The AAPS Journal - October 4, 2022 Category: Drugs & Pharmacology Source Type: research
Phish-Pharm: A Searchable Database of Pharmacokinetics and Drug Residue Literature in Fish — 2022 Update
AbstractA new version of Phish-Pharm: a Searchable Database of Pharmacokinetics and Drug Residue Literature in Fish has been updated and posted online at:http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/Phish-Pharm/default.htm. The new version contains over 700 articles encompassing 191 aquatic species (fish, shellfish, and more).Phish-Pharm, first released in 2005, accompanied an article in this Journal, titled “Fish Drug Analysis—Phish-Pharm: A Searchable Database of Pharmacokinetics Data in Fish,” by R. Reimschuessel, L. Stewart, E. Squibb, K. Hirokawa, T. Brady, D. Brooks, B. Shaikh, C. Hodsdon,...
Source: The AAPS Journal - October 4, 2022 Category: Drugs & Pharmacology Source Type: research
NIR Spectroscopy as an Online PAT Tool for a Narrow Therapeutic Index Drug: Toward a Platform Approach Across Lab and Pilot Scales for Development of a Powder Blending Monitoring Method and Endpoint Determination
Abstract
An online near-infrared (NIR) spectroscopy platform system for real-time powder blending monitoring and blend endpoint determination was tested for a phenytoin sodium formulation. The study utilized robust experimental design and multiple sensors to investigate multivariate data acquisition, model development, and model scale-up from lab to manufacturing. The impact of the selection of various blend endpoint algorithms on predicted blend endpoint (i.e., mixing time) was explored. Spectral data collected at two process scales using two NIR spectrometers was incorporated in a single (global) calibration model. Un...
Source: The AAPS Journal - September 28, 2022 Category: Drugs & Pharmacology Source Type: research
Chemistry Manufacturing and Controls Development, Industry Reflections on Manufacture, and Supply of Pandemic Therapies and Vaccines
AbstractThis publication provides some industry reflections on experiences from the Chemistry, Manufacturing, and Controls (CMC) development and manufacture and supply of vaccines and therapies in response to the COVID-19 pandemic. It integrates these experiences with the outcomes from the collaborative work between industry and regulators in recent years on innovative science- and risk-based CMC strategies to the development of new, high-quality products for unmet medical needs. The challenges for rapid development are discussed and various approaches to facilitate accelerated development and global supply are collated fo...
Source: The AAPS Journal - September 27, 2022 Category: Drugs & Pharmacology Source Type: research
Neutralization Activity of Anti-drug Antibodies Against a Biotherapeutic Can Be Predicted from a Comprehensive Pharmacokinetics, Pharmacodynamics, and Anti-drug Antibody Data Analysis
AbstractHistorically, a neutralization antibody (NAb) assay is considered critical in immunogenicity assessment of biologic therapeutics, even with low anti-drug antibody (ADA) positive rates. In 2019, FDA new guidelines issued on immunogenicity testing acknowledged the possibility of using “a highly sensitive PD marker or an appropriately designed PK assay or both that generate data that inform clinical activity” to replace a NAb assay. In the current manuscript, we present data for PK, PD, and ADA assays which collectively succeed to replace the standalone NAb assay. The data inc lude a total LC/MS-based PK assay, a ...
Source: The AAPS Journal - September 27, 2022 Category: Drugs & Pharmacology Source Type: research
Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma
This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody. Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we dev...
Source: The AAPS Journal - September 20, 2022 Category: Drugs & Pharmacology Source Type: research
Sinusoidal Organic Anion-Transporting Polypeptide 1B1/1B3 and Bile Canalicular Multidrug Resistance-Associated Protein 2 Play an Essential Role in the Hepatobiliary Disposition of a Synthetic Cyclic Dinucleotide (STING Agonist)
In this study, we used ML00960317 (synthetic STING agonist) to investigate the hepatobiliary disposition of this novel molecular entity. A bile-duct cannulated (BDC) rat study indicated that biliary excretion is the major route of elimination for ML00960317 (84% of parent dose in bile). The human biliary clearance usingin vitro sandwich cultured human hepatocyte model predicted significant biliary excretion of ML00960317 (biliary excretion index (BEI) of 47%). Moreover, the transport studies using transporter expressing cell lines, hepatocytes, and membrane vesicles indicated that ML00960317 is a robust substrate of OATP1B...
Source: The AAPS Journal - September 19, 2022 Category: Drugs & Pharmacology Source Type: research
Usage of Compartmental Models in Predicting COVID-19 Outbreaks
AbstractAccurately predicting the spread of the SARS-CoV-2, the cause of the COVID-19 pandemic, is of great value for global regulatory authorities to overcome a number of challenges including medication shortage, outcome of vaccination, and control strategies planning. Modeling methods that are used to simulate and predict the spread of COVID-19 include compartmental model, structured metapopulations, agent-based networks, deep learning, and complex network, with compartmental modeling as one of the most widely used methods. Compartmental model has two noteworthy features, a flexible framework that allows users to easily ...
Source: The AAPS Journal - September 2, 2022 Category: Drugs & Pharmacology Source Type: research
Comparing a Bayesian Approach (BEST) with the Two One-Sided t-Tests (TOSTs) for Bioequivalence Studies
AbstractThe two one-sidedt-tests (TOST) procedure has been used to evaluate average bioequivalence (BE). As a regulatory standard, it is crucial that TOST distinguish BE from not-BE (NBE) when BE data are not lognormal. TOST was compared with a Bayesian procedure (BEST by Kruschke) in simulated datasets of test/reference ratios (T/R) which were BE and NBE, wherein (1) log(T/R) or T-R were normally distributed, (2) sample sizes ranged 10 –50, and (3) extreme log(T/R) or T-R values were randomly included in datasets. The 90% “credible interval” (CrI) from BEST is a Bayesian alternative of the 90% confidence interval (C...
Source: The AAPS Journal - September 1, 2022 Category: Drugs & Pharmacology Source Type: research
Correction to: Cell-Based Therapies Formulations: Unintended Components
(Source: The AAPS Journal)
Source: The AAPS Journal - August 30, 2022 Category: Drugs & Pharmacology Source Type: research
