Modelling Based Approaches to Support Generic Drug Regulatory Submissions-Practical Considerations and Case Studies
We describe herein approaches and common pitfalls while submitting model based justifications as a response to the regulatory deficiencies during the generic drug development process. With some in-house case studies, we have attempted to provide a clear path for PBPK model based justifications for bio-waivers. With this review, the gap between theoretical knowledge and practical application of modelling and simulation tools for generic drug product development could be potentially reduced.Graphical abstract (Source: The AAPS Journal)
Source: The AAPS Journal - June 23, 2023 Category: Drugs & Pharmacology Source Type: research
Mini-PBPK-Based Population Model and Covariate Analysis to Assess the Complex Pharmacokinetics and Pharmacodynamics of RO7449135, an Anti-KLK5/KLK7 Bispecific Antibody in Cynomolgus Monkeys
AbstractRO7449135, an anti-kallikrein (KLK)5/KLK7 bispecific antibody, is in development as a potential therapy against Netherton ’s syndrome (NS). In cynomolgus monkey studies, RO7449135 bound to KLK5 and KLK7, causing considerable accumulation of total KLKs, but with non-dose-proportional increase. To understand the complex PKPD, a population model with covariate analysis was developed accounting for target binding in skin and migration of bound targets from skin to blood. The covariate analysis suggested the animal batch as the categorical covariate impacting the different KLK5 synthesis rates between the repeat-dose ...
Source: The AAPS Journal - June 23, 2023 Category: Drugs & Pharmacology Source Type: research
Evaluation of the Potential for Drug-Drug Interactions with Inhaled Itraconazole Using Physiologically Based Pharmacokinetic Modelling, Based on Phase 1 Clinical Data
AbstractItraconazole 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 “victim drug.” The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharm...
Source: The AAPS Journal - June 21, 2023 Category: Drugs & Pharmacology Source Type: research
Multifaceted Approach for Quantification and Enzymatic Activity of Iduronate-2-Sulfatase to Support Developing Gene Therapy for Hunter Syndrome
In conclusion, the multifaceted bioanalytical method for I2S and its enzymatic activity were established to assess gene therapy products in Hunter syndrome.Graphical abstract (Source: The AAPS Journal)
Source: The AAPS Journal - June 20, 2023 Category: Drugs & Pharmacology Source Type: research
Streamlining Food Effect Assessment — Are Repeated Food Effect Studies Needed? An IQ Analysis
AbstractCurrent regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food E...
Source: The AAPS Journal - June 15, 2023 Category: Drugs & Pharmacology Source Type: research
Correction: A Tangeretin Derivative Inhibits the Growth of Human Prostate Cancer LNCaP Cells by Epigenetically Restoring p21 Gene Expression and Inhibiting Cancer Stem-like Cell Proliferation
(Source: The AAPS Journal)
Source: The AAPS Journal - June 13, 2023 Category: Drugs & Pharmacology Source Type: research
Correction: Harmonizing Biopredictive Methodologies Through the Product Quality Research Institute (PQRI) Part I: Biopredictive Dissolution of Ibuprofen and Dipyridamole Tablets
(Source: The AAPS Journal)
Source: The AAPS Journal - June 8, 2023 Category: Drugs & Pharmacology Source Type: research
Anti-melanoma Effects of Resiquimod (RSQ) In Vitro and in Combination with Immune Checkpoint Blockade In Vivo
In conclusion, the combination of RSQ and anti-PD-1 may be a promising treatment for melanoma patients, especially as both treatments have already been used independently to safely treat melanoma patients.Graphical Abstract (Source: The AAPS Journal)
Source: The AAPS Journal - June 2, 2023 Category: Drugs & Pharmacology Source Type: research
Population-Based Pharmacodynamic Modeling of Omalizumab in Pediatric Patients with Moderate to Severe Persistent Inadequately Controlled Allergic Asthma
The objective of this study was to quantitatively characterize the relationship between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) inpediatrics using a population-based pharmacodynamic model. Data collected during the steroid-stable period (first 24 weeks) of an omalizumab trial with pediatric asthma patients (Study IA05) were used to build the pediatric IgE –FEV1 model. The previously developed population IgE–FEV1 model in adults/adolescents was adapted to characterize the FEV1 and IgE relationship in pediatrics with different magnitude and onset of response. The pedi...
Source: The AAPS Journal - June 2, 2023 Category: Drugs & Pharmacology Source Type: research
Survey Outcome on Immunogenicity Risk Assessment Tools for Biotherapeutics: an Insight into Consensus on Methods, Application, and Utility in Drug Development
AbstractA survey conducted by the Therapeutic Product Immunogenicity (TPI) community within the American Association of Pharmaceutical Scientists (AAPS) posed questions to the participants on their immunogenicity risk assessment strategies prior to clinical development. The survey was conducted in 2 phases spanning 5 years, and queried information aboutin silico algorithms andin vitro assay formats for immunogenicity risk assessments and how the data were used to inform early developability effort in discovery, chemistry, manufacturing and control (CMC), and non-clinical stages of development. The key findings representi...
Source: The AAPS Journal - June 2, 2023 Category: Drugs & Pharmacology Source Type: research
Impact of Organ Impairment on the Pharmacokinetics of Therapeutic Peptides and Proteins
In this study, we reviewed how often therapeutic peptides and proteins were assessed for the effect of RI and HI on PK, the findings, and the resulting labeling recommendations. RI effects were reported in labeling for 30 (57%) peptides and 98 (39%) proteins and HI effects for 20 (38%) peptides and 55 (22%) proteins. Dose adjustments were recommended for RI in 11 of the 30 (37%) peptides and 10 of the 98 (10%) proteins and for HI in 7 of the 20 (35%) peptides and 3 of the 55 (5%) proteins. Additional actionable labeling includes risk mitigation strategies; for example, some product labels have recommended avoid use or ...
Source: The AAPS Journal - May 26, 2023 Category: Drugs & Pharmacology Source Type: research
Micellar Encapsulation of Propofol Reduces its Adsorption on Extracorporeal Membrane Oxygenator (ECMO) Circuit
AbstractExtracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass device used on critically ill patients with refractory heart and lung failure. Patients supported with ECMO receive numerous drugs to treat critical illnesses and the underlying diseases. Unfortunately, most drugs prescribed to patients on ECMO lack accurate dosing information. Dosing can be variable in this patient population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Propofol is a widely used anesthetic in ECMO patients and is known to have high adsorption rates in ECMO circuits due...
Source: The AAPS Journal - May 25, 2023 Category: Drugs & Pharmacology Source Type: research
Predicting Human Bioavailability of Subcutaneously Administered Monoclonal Antibodies Using Non-human Primate Linear Clearance and Antibody Isoelectric Point
In this study, we predicted human SC bioavailability of mAbs using preclinical data only by two approaches. In the first approach, allometric scaling was used to predict human linear CL from non-human primate (NHP) linear CL. The predicted human CL and the pI of the whole antibody or Fv regions were then incorporated into two previously published MLR models to predict the human bioavailability of 61 mAbs. In the second approach, two MLR models were developed using NHP linear CL and the pI of whole antibody or Fv regions of 41 mAbs in a training set. The two models were validated using an independent test dataset containing...
Source: The AAPS Journal - May 25, 2023 Category: Drugs & Pharmacology Source Type: research
Amgen v. Sanofi: Critical Impact on the Value of Innovative Science in Antibody Discovery
(Source: The AAPS Journal)
Source: The AAPS Journal - May 12, 2023 Category: Drugs & Pharmacology Source Type: research
A Precise qNMR Method for the Rapid Quantification of Lot-to-Lot Variations in Multiple Quality Attributes of Pentosan Polysulfate Sodium
AbstractPentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to yield a mixture of 4 –6 kDa polysaccharides. The chain is mainly composed of sulfated xylose (Xyl) with branched 4-O-methyl-glucuronate (MGA). During generic drug development, the quality attributes (QAs) including monosaccharide composition, modification, and length need to be comparable to those found in the refere nce list drug (RLD). However, the range of QA variation of the RLD PPS has not been well characterized. Here, multiple PPS RLD lots ...
Source: The AAPS Journal - May 6, 2023 Category: Drugs & Pharmacology Source Type: research
