Accelerated Development of Pharmaceuticals Past, Present, and Future.

This paper reviews the accelerated development of pharmaceuticals, exploring past, present, and future perspectives. It provides a historical overview of early strategies used to expedite development, beginning with initiatives from the 1990s. The work of Gardner and Byrn in accelerated development analysis during this era is highlighted. The narrative progresses to the 2000s, discussing the emergence of PK/PD in accelerating pharmaceutical development. The paper further examines case studies in the accelerated development field, including the INDIGO and Chorus programs. It concludes with an analysis of the current state of the field, referencing the NIPTE conference, which focused on the industrial perspective of accelerated development. Additionally, the paper outlines strategies for the rapid development of Solid Lipid Nanoparticle manufacturing and vaccine production.

Night Warming Has Mixed Effects on the Development of the Fall Armyworm, Spodoptera frugiperda (Lepidoptera, Noctuidae), in Southern China.

The Fall Armyworm, Spodoptera frugiperda (Lepidoptera, Noctuidae), is a serious migratory pest. After invading China in 2019, the species was established as a year-round breeding population in most of the southern provinces. The area of winter maize in this region has been increasing due to the huge demand of fresh maize consumption, which is potentially at risk from this invasive pest, although the growth and development of S. frugiperda in the region's changing climate is unclear, particularly with rising temperatures at night. Here, we used the highest daytime temperatures of 27 °C, 24 °C, 20 °C and decreased these by 2, 4 and 6 °C to reflect the range of nighttime temperatures indicative of winter conditions in a warming climate to evaluate the effect of increasing night temperatures on the growth and development of S. frugiperda. Results show that the survival of larvae and pupae significantly declined with daytime temperatures declining and the nighttime temperature range increasing. Significant developmental effects were observed across all daytime-nighttime temperature treatments, except for adults. Additionally, there were significant interaction effects for all stages, except the egg stage, and generation time. The development rate increased with the increasing daytime temperatures and nighttime temperatures, except for the intermediate treatments (Group II). The uniformity of pupation and emergence times were higher under high daytime temperatures and nighttime temperature treatments. Predictions of FAW development and warnings to local farmers need to be adjusted to take into account the more rapid development when nighttime temperatures increase in the warming climate. These results will support decision makers in developing long-term management strategies for FAW in southern China.

Accelerated cell culture process development and characterization for cilgavimab/tixagevimab (AZD7442) for the prevention and treatment of COVID-19.

The global COVID-19 pandemic ignited an unprecedented race to develop vaccines and antibody therapeutics. AstraZeneca's pursuit to provide AZD7442 (EVUSHELD), two long-acting, SARS-CoV-2 spike receptor binding domain-specific neutralizing monoclonal antibodies, to individuals at risk on highly accelerated timelines challenged our traditional ways of process development and spurred the rapid adoption of novel approaches. Conventional upstream development processes were replaced by agile strategies that combined technological advances and highly accelerated workflows. With calculated business risks and close cross-functional collaborations, this process paved the way for hyper accelerated antibody development from discovery through manufacturing, process validation, emergency use authorization filing, and global regulatory approvals. The result was initiation of commercial manufacturing at a contract manufacturing organization less than 6 months from the selection of cilgavimab and tixagevimab-a process that historically has taken close to 10 years.

Does pubertal stage mediate the association between family environment and structure and function of the amygdala-mPFC circuit? A replication study of the longitudinal ABCD cohort.

Psychosocial acceleration theory suggests that early stress accelerates pubertal development. Using half of the baseline Adolescent Brain and Cognitive Development (ABCD) cohort, Thijssen et al. (2020) provide support that accelerated puberty following stressful family environments may promote neurodevelopment. Here, we replicate and extend those analyses using 1) data from the second half of the ABCD sample (n = 3300 +, ages 9-10), and 2) longitudinal imaging data from the original sample (n = 1800 +, ages 11-12). A family environment latent variable was created and related to anterior cingulate cortex (ACC) thickness, area, white matter fractional anisotropy, amygdala volume, and cingulo-opercular network (CON)-amygdala resting-state functional connectivity. Results from the independent sample replicate the mediating effects of family environment through pubertal stage on amygdala-CON functional connectivity. Sex-stratified analyses show indirect effects via pubertal stage in girls; boys show evidence for direct associations. Analyses using wave 2 imaging data or wave 2-wave 1 difference scores from the originally-analyzed sample replicate the resting-state indirect effects. The current paper replicates the mediating role for puberty in the association between family environment and neurodevelopment. As both direct and indirect associations were found, puberty may be one of multiple mechanisms driving accelerated neurodevelopment following environmental stress.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

Release Mechanisms and Practical Percolation Threshold for Long-acting Biodegradable Implants: An Image to Simulation Study.

The development of long-acting drug formulations requires efficient characterization technique as the designed 6-12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions  using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance.  It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.

Pubertal development mediates the association between family environment and brain structure and function in childhood.

Psychosocial acceleration theory suggests that pubertal maturation is accelerated in response to adversity. In addition, suboptimal caregiving accelerates development of the amygdala-medial prefrontal cortex circuit. These findings may be related. Here, we assess whether associations between family environment and measures of the amygdala-medial prefrontal cortex circuit are mediated by pubertal development in more than 2000 9- and 10-year-old children from the Adolescent Brain Cognitive Development Study (http://dx.doi.org/10.15154/1412097). Using structural equation modeling, demographic, child-reported, and parent-reported data on family dynamics were compiled into a higher level family environment latent variable. Magnetic resonance imaging preprocessing and compilations were performed by the Adolescent Brain Cognitive Development Study's data analysis core. Anterior cingulate cortex (ACC) thickness, area, white matter fractional anisotropy, amygdala volume, and cingulo-opercular network-amygdala resting-state functional connectivity were assessed. For ACC cortical thickness and ACC fractional anisotropy, significant indirect effects indicated that a stressful family environment relates to more advanced pubertal stage and more mature brain structure. For cingulo-opercular network-amygdala functional connectivity, results indicated a trend in the expected direction. For ACC area, evidence for quadratic mediation by pubertal stage was found. Sex-stratified analyses suggest stronger results for girls. Despite small effect sizes, structural measures of circuits important for emotional behavior are associated with family environment and show initial evidence of accelerated pubertal development.

Maternal care in infancy and the course of limbic development.

Maternal care may predict limbic development, though relations may vary by age and type of assessment. Here, we examined maternal behavior during early infancy (i.e., six months postpartum) in relation to offspring hippocampal and amygdala volume and microstructure development between 4.5 (n = 99) and 6 (n = 111) years. In interaction with offspring sex, maternal sensitivity predicted left amygdala volume at 6.0 years (ß=-0.214, p = 0.032, df = 89) and independently predicted predominately left lateralized aspects of amygdala and hippocampal microstructure at both time points (hippocampus: left FA at 4.5 years [ß=-0.241, p = 0.043, df = 68], and, in interaction with sex, left [(ß = 0.349, p = 0.022, df = 86) and right FA at 6 years (ß = 0.357, p = 0.016, df = 86] and left MD growth [ß = -0.517, p = 0.021, df = 37]; amygdala: left MD at 4.5 years [ß = -0.319, p = 0.007, df = 69] and, in interaction with offspring sex, left MD growth [ß = -0.546, p = 0.019, df = 37]). Results suggest exposure to non-extreme, early insensitive care impacts neuroanatomy important to learning and stress regulation, perhaps by accelerating development. This underscores the need to promote sensitive caregiving during early infancy within community samples.

Greater caregiving risk, better infant memory performance?

Poor early life care often relates to cognitive difficulties. However, newer work suggests that in early-life, adversity may associate with enhanced or accelerated neurodevelopment. We examine associations between postnatal caregiving risks (i.e., higher self-reported postnatal-anxiety and lower observed maternal sensitivity) and infant relational memory (i.e., via deferred imitation and relational binding). Using subsamples of 67-181 infants (aged 433-477 post-conceptual days, or roughly five to seven months since birth) taking part in the GUSTO study, we found such postnatal caregiving risk significantly predictive of "better" performance on a relational binding task following a brief delay, after Bonferroni adjustments. Subsequent analyses suggest that the association between memory and these risks may specifically be apparent among infants spending at least 50% of their waking hours in the presence of their mothers. Our findings echo neuroimaging research concerning similar risk exposure and larger infant hippocampal volume, and likewise underscore the importance of considering developmental context in understanding early life experience. With this in mind, these findings caution against the use of cognitive outcomes as indices of experienced risk.

Developing WHO rapid advice guidelines in the setting of a public health emergency.

OBJECTIVES: We describe newly established guidance for guideline developers at the World Health Organization (WHO) on the process and procedures for developing a rapid advice guideline in the context of a public health emergency (e.g., the 2014 Ebola epidemic). STUDY DESIGN AND SETTING: We based our approach on established rapid review methods, which were incorporated into existing WHO guideline development processes. Guidance was further informed by in-depth discussions of issues related to rapid guideline development with WHO staff (n = 6), who oversee the Organization's response to emergencies. RESULTS: We discuss criteria for considering if a rapid advice guideline is appropriate and feasible and outline the roles of various contributors across the phases of development. Further, we describe the methods and steps involved in performing rapid reviews, which are more fluid and iterative than for a standard guideline process. In general, rapid advice guidelines involve a shorter timeline, narrower scope, and the use of abbreviated methods for the evidence review. CONCLUSION: Important differences exist between developing a standard guideline and a rapid advice guideline. However, the core principles for WHO guidelines apply to rapid advice guidelines including minimizing bias, applying transparent processes and the use of explicit methods.

Environmental concentration of carbamazepine accelerates fish embryonic development and disturbs larvae behavior.

Environmental pollution caused by pharmaceuticals has been recognized as a major threat to the aquatic ecosystems. Carbamazepine, as the widely prescribed antiepileptic drug, has been frequently detected in the aquatic environment and has created concerns about its potential impacts in the aquatic organisms. The effects of carbamazepine on zebrafish embryos were studied by examining their phenotype, behavior and molecular responses. The results showed that carbamazepine disturbed the normal growth and development of exposed zebrafish embryos and larvae. Upon exposure to carbamazepine at 1 µg/L, the hatching rate, body length, swim bladder appearance and yolk sac absorption rate were significantly increased. Embryos in treatment groups were more sensitive to touch and light stimulation. At molecular level, exposure to an environmentally relevant concentration (1 µg/L) of carbamazepine disturbed the expression pattern of neural-related genes of zebrafish embryos and larvae. This study suggests that the exposure of fish embryo to antiepileptic drugs, at environmentally relevant concentrations, affects their early development and impairs their behavior. Such impacts may have future repercussions by affecting fish population structure.