Challenging the Norm:A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics

The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.</p

Challenging the Norm:A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics

The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.</p

Challenging the Norm:A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics

The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.</p

Antiquarianism, Local Traditions and Urban Identity in the Early Modern Netherlands:the Controversy about the City of the Nervii

In the 16th and 17th centuries, the study of Roman remains led to the questioning of many local traditions, as these which associated the episcopal see of Tournai with the valiant Nervii. The rediscovery of ancient Itineraries and the absence of vestiges in Tournai led scholars to question this association: they preferred to locate the city of the Nervii in Bavay. This new thesis irritated several Tournaisian authors who defended the illustrious past of their city. This scholarly polemic illustrates the new role that the material evidence played in the construction of historical discourses and local identity at that time.During the Middle Ages and the early modern period, the antiquity of a cityor a region played a considerable role in the construction of the collective identity of its inhabitants. The more ancient a community’s origin, the moreit was regarded as prestigious and admirable.1 It was particularly common for cities or regions to claim to date back to Roman times. This period was prized for two reasons: first, the idea of power and refinement associated with ancient Rome was a source of fascination during the Renaissanceera and, second, it was, in many areas, the oldest past known through writtenor material sources.</p

Modeling second harmonic generation at alcohol/air interfaces. A molecular multi-layer approach

The liquid/air interface asymmetry leads to specific molecular interactions, compared to those observed in the bulk, and its characterization has significant implications for describing and controlling chemical and physical processes inherent to catalysis and environmental sciences. The second harmonic generation (SHG) is an interfacial selective spectroscopy often used to characterize interfaces. In this study, a computational multiscale methodology that combines molecular dynamics and quantum chemistry calculations has been worked out to scrutinize the SHG responses of 1-alcohols/air interfaces, and to unravel the role of the aliphatic chain length by exploring alcohols ranging from ethanol to pentanol. First, their molecular responses (β, the first hyperpolarizability) and then their macroscopic responses (χ 2, the second-order NLO susceptibility) have been computed and analyzed by decomposing the global responses into the contributions of successive molecular layers, providing relationships between the structure of the interfacial molecules and their dipolar SHG responses. The results show (i) an enhancement of the β ZZZ component (the component perpendicular to the interface) attributed to collective responses arising from the structural alignment of the interfacial molecules. Furthermore, (ii) longer aliphatic chains tend to create a bilayer structure, which was clearly observed at the pentanol/air interface where the polar heads of the molecules in the first and second molecular layers point toward each other. Such structural organization leads to a partial centrosymmetry at the interface, which is detrimental to the dipolar SHG response. On the other hand, (iii) owing to their smaller number density, the χ ZZZ 2 response of longer alcohols is smaller than for the smaller ones. Furthermore, (iv) a correlation between χ ZXX 2 and the aliphatic chain length is observed for the third molecular layer.</p

Modeling second harmonic generation at alcohol/air interfaces. A molecular multi-layer approach

The liquid/air interface asymmetry leads to specific molecular interactions, compared to those observed in the bulk, and its characterization has significant implications for describing and controlling chemical and physical processes inherent to catalysis and environmental sciences. The second harmonic generation (SHG) is an interfacial selective spectroscopy often used to characterize interfaces. In this study, a computational multiscale methodology that combines molecular dynamics and quantum chemistry calculations has been worked out to scrutinize the SHG responses of 1-alcohols/air interfaces, and to unravel the role of the aliphatic chain length by exploring alcohols ranging from ethanol to pentanol. First, their molecular responses (β, the first hyperpolarizability) and then their macroscopic responses (χ 2, the second-order NLO susceptibility) have been computed and analyzed by decomposing the global responses into the contributions of successive molecular layers, providing relationships between the structure of the interfacial molecules and their dipolar SHG responses. The results show (i) an enhancement of the β ZZZ component (the component perpendicular to the interface) attributed to collective responses arising from the structural alignment of the interfacial molecules. Furthermore, (ii) longer aliphatic chains tend to create a bilayer structure, which was clearly observed at the pentanol/air interface where the polar heads of the molecules in the first and second molecular layers point toward each other. Such structural organization leads to a partial centrosymmetry at the interface, which is detrimental to the dipolar SHG response. On the other hand, (iii) owing to their smaller number density, the χ ZZZ 2 response of longer alcohols is smaller than for the smaller ones. Furthermore, (iv) a correlation between χ ZXX 2 and the aliphatic chain length is observed for the third molecular layer.</p

Antiquarianism, Local Traditions and Urban Identity in the Early Modern Netherlands:the Controversy about the City of the Nervii

In the 16th and 17th centuries, the study of Roman remains led to the questioning of many local traditions, as these which associated the episcopal see of Tournai with the valiant Nervii. The rediscovery of ancient Itineraries and the absence of vestiges in Tournai led scholars to question this association: they preferred to locate the city of the Nervii in Bavay. This new thesis irritated several Tournaisian authors who defended the illustrious past of their city. This scholarly polemic illustrates the new role that the material evidence played in the construction of historical discourses and local identity at that time.During the Middle Ages and the early modern period, the antiquity of a cityor a region played a considerable role in the construction of the collective identity of its inhabitants. The more ancient a community’s origin, the moreit was regarded as prestigious and admirable.1 It was particularly common for cities or regions to claim to date back to Roman times. This period was prized for two reasons: first, the idea of power and refinement associated with ancient Rome was a source of fascination during the Renaissanceera and, second, it was, in many areas, the oldest past known through writtenor material sources.</p