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Review of the Technical, Toxicological, and PKPD Considerations for Conducting Inhalation Toxicity Studies on Biologic Pharmaceuticals—The Outcome of a Cross-Industry Working Group Survey
No full textThe inhaled route is still a relatively novel route for delivering biologics and poses additional challenges to those encountered with inhaled small molecules, further complicating the design and interpretation of toxicology studies. A working group formed to summarize the current knowledge of inhaled biologics across industry and to analyze data collated from an anonymized cross-industry survey comprising 12 inhaled biologic case studies (18 individual inhalation toxicity studies on monoclonal antibodies, fragment antibodies, domain antibodies, oligonucleotides, and proteins/peptides). The output of this working group provides valuable insights into the issues faced when conducting toxicology studies with inhaled biologics, including common technical considerations on aerosol generation, use of young and sexually mature nonhuman primates, pharmacokinetic/pharmacodynamic modeling, exposure and immunogenicity assessment, maximum dose setting, and no observed adverse effect levels determination. Although the current data set is too small to allow firm conclusions, testing of novel biologics remains an active area and is likely to remain so for molecules where delivery via the inhaled route is beneficial. In the future, it is hoped others will continue to share their experiences and build on the conclusions of this review to further improve our understanding of these complex issues and, ultimately, facilitate the safe introduction of inhaled biologics into clinical use
The effectiveness of quality control samples in pharmaceutical bioanalysis
No full textThe use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs. Analysis of data collected across organizations, molecular types and analytical platforms, revealed that bioanalytical methods are very reproducible; and that QC samples improve the overall quality of pharmacokinetic concentration data and justifies their continued use
The Use of Phospholipids to make Pharmaceutical Form Line Extensions
No full textThis review describes the use of phospholipid excipients to make Pharmaceutical Form (Dosage Form) Line Extensions of existing drugs. as part of a Product Life Cycle. We provide product examples and development candidates, which show the versatility of phospholipids as key excipients in formulations to develop line extension drug products for any administration route by reformulating existing products. The resulting products enable the application of a drug substance for another administration route or show an increased efficacy and/or reduced toxicity of the formulated drug substances, or enable a more convenient use, through reduction of dosing frequency, or adapt a product for regulatory requirements for specific patient populations. The patents related to the product examples are used to protect the substantially improved products. Parenteral line extensions for lipophilic drugs using non-toxic phospholipid-based solubilising formulations are clearly a better alternative to products with solubilising synthetic detergents with anaphylactic properties
Pharmacological inhibition of IKKβ dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1
No full textThe NLRP3 inflammasome is a critical component of the innate immune response to sterile inflammation. Its regulation involves a priming step, required for up-regulation of inflammasome protagonists and an activation step leading to NLRP3 inflammasome complex assembly, which triggers caspase-1 activity. The IκKβ kinase regulates canonical NF-κB, a key pathway involved in transcriptional priming. We found that IκKβ also regulates the activation and function of the NLRP3 inflammasome. Two unrelated IκKβ inhibitors, AFN700 and TPCA-1, when applied after priming, fully prevented IL-1β secretion triggered by nigericin in THP-1 cells. Both inhibitors prevented neither inflammasome assembly, as monitored by measuring the formation of ASC specks, nor the generation of caspase-1 p20, a hallmark of caspase-1 activity, but they impaired the initial cleavage and activation of procaspase-1. These data thus indicate that IκKβ activity is required for efficient activation of NLRP3, suggesting that IκKβ may fulfill a dual role in coupling priming and activation of the NLRP3 inflammasome
Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates
No full textObtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9 L (70 kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13–26% CV and 15–35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs
Chemoproteomics-Enabled Ligand Screening Yields Covalent RNF114-Based Degraders that Mimics Natural Product Function
No full textThe translation of natural product function to fully synthetic small molecules has remained an important process in medicinal chemistry for decades resulting in numerous FDA-approved medicines. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation (TPD) ¬– a powerful therapeutic modality within modern day drug discovery. Using activity-based protein profiling-enabled covalent ligand screening approaches, we herein realize the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading oncology targets such as BRD4 and BCR-ABL in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology
BET bromodomain inhibitors regulate keratinocyte plasticity
No full textAlthough most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class. [Figure not available: see fulltext.
The influence of particle size on the application of compression and compaction models for tableting
No full textThe physical characteristics of raw materials determine powder compression and compaction performance as
relevant in pharmaceutical processes. For instance, the influence of initial particle size on powder compression
and the resulting strength of specimen are highly complex and are still not sufficiently understood. Existing
studies are often limited to materials with well-defined deformation behaviour, such as purely brittle or ductile.
However, the deformation behaviour of active pharmaceutical ingredients (APIs) is often more complex. In this
study, the influence of initial particle size on powder compressibility and compactibility is systematically
characterized by consideration of in-die compressibility, specific energies, quick elastic recovery, tablet porosity
and, tensile strength for the binder microcrystalline cellulose and three APIs. The decrease of particle size leads
to an increase of the resistance against compression by trend and probably to a different contribution of the
acting deformation mechanisms. The compactibility is increased with decreasing particle size because of the
increasing number of bonds in a cross-sectional area of the tablet, as found by the application of the model of
Rumpf. Furthermore, it is found that the model of Rumpf combined with the JKR model provides a meaningful
property function to estimate tablet tensile strength
Statistically significant versus practically relevant trend in stability data
No full textHow to decide whether a statistically significant trend is of practical relevance? In the context of stability data of pharmaceuticals, this publication provides a way forward to use different measures of (method) variability to compare to the observed changes over time. A panel of analytical experts assessed whether statistical significant trends were of practical relevance or not. For different types of assessing variability, recommendations for decision criteria were derived that best match these assessments i.e. finding a suited balance between not detecting a relevant trend and between flagging a trend wrongly as relevant. For this purpose, more than 60 data sets from Biosimilar projects of Sandoz/Novartis were leveraged. Hence, this paper provides a scientific way for an assessment whether a statistically significant trend is of practical relevance or not and a case study is presented and discussed
Cantharidin-induced skin blister as an in vivo model of inflammation.
No full textThe cantharidin-induced skin blister is a simple model for investigating cell migration and inflammatory mediator production at a site of inflammation. Application of cantharidin solution to the ear pinna results in formation of a blister with cell influx and induction of inflammatory mediators at the skin site, as well as local swelling of the ear pinna. The model can be used for investigating anti-inflammatory compounds, such as dexamethasone, and for preclinical drug discovery research, especially in areas where neutrophilic inflammation plays a role in disease pathophysiology. The cantharidin blister model is one of very few translational models described in humans, and the mechanism of inflammation induction is comparable in mice and man. In human studies, the cantharidin blister assay has been used to assess the effects of potential new therapies in early-stage clinical studies