Charles River has a long history of experience in the field of respiratory disease research. Our expert scientists provide a wide range of capabilities to support our clients’ drug discovery programs from early discovery to IND-enabling safety. We have great expertise and one of the largest capacities for inhalation toxicology studies in the world. We offer seamless, one-stop service from early target identification to GLP toxicology and delivery of target engagement biomarkers into clinical development.
Charles River offers animal models specific for respiratory research such as the Brown Norway Rat. And, if your research requires the use of specialized or genetically modified models, our experts will work with you to customize and create them for your study using the latest model creation technologies.
Basic Research Products and Services
Chronic respiratory diseases are among the leading causes of death around the world, making the pursuit of respiratory therapies an area of intense interest. Effective respiratory disease drug discovery requires a thorough understanding of the disease as well as the drivers on a cellular level to target the appropriate molecular mechanism. Disease-relevant in vitro and in vivo models combined with appropriate biomarkers, and both compound formulation and dosage routes are carefully considered. Charles River has a long history of experience with all aspects of respiratory therapy research – from discovery and optimization of novel compounds and efficacy evaluation to safety evaluation by all clinical routes, including inhalation. Since 2001, scientists working on integrated respiratory disease drug discovery programs with our partners have been named as co-inventors on approximately 70 patents for novel compounds for respiratory indications and have delivered over 25 preclinical development candidates in this area. They can help you manage the unique challenges associated with your respiratory discovery program.
In Vitro Assay Development and Screening
Our scientists have extensive experience in the development and execution of novel in vitro assays, including successful assay transfer of target engagement biomarkers from our laboratories into phase I/II studies. Additionally, we have developed a panel of disease-relevant assays in human primary cells, including disease material, allowing investigation of mechansims of interest across a variety of disease conditions
Medicinal Chemistry and Pharmaceutics
Many respiratory therapies are designed to be efficacious when administered via intranasal or inhaled routes, and compounds must be designed with specific physiochemical properties to be delivered in this way. Our teams have a lengthy track record of delivering successful candidate drugs for respiratory indications, with a detailed understanding of the design of inhaled compounds and the requirements for profiling and optimizing these compounds to ensure compatibility with delivery devices, excipients, and other potential combination therapies components.
In Vivo Pharmacology Studies
Our validated rodent models, combined with appropriate target engagement biomarkers, provide rapid, cost-effective methods for evaluating the efficacy of novel anti-inflammatory, anti-fibrotic, and bronchodilator agents targeting asthma, pulmonary fibrosis, pneumonia, and diseases marked by neutrophil recruitment (e.g., acute respiratory distress syndrome, cystic fibrosis, chronic obstructive pulmonary disease) via both inhaled and systemic routes.
In Vitro and In Vivo PK Screening
PK screening is a necessary component of in the design and testing of compounds targeting the lung, and where inhaled delivery is used as the route of administration, specialized screens and assays are required. Our teams have extensive experience with this aspect of inhaled drug discovery, with extensive knowledge of the drivers required to deliver an optimized compound.
In Vitro Toxicity Testing
MucilAir™ is a mucus-secreting, ciliated epithelial model of the human airway produced by Epithelix Sàrl, Switzerland. Derived from human airway cells collected from healthy donors and cultured at the air interface on permeable membranes, its morphology and functions mirror the tracheobronchial epithelium, making it an ideal model to identify potential airway toxicants in candidate molecules. We are also able to de-risk projects investigating, for example, particulate cytotoxicity and neutrophil-mediated bacterial killing.
In Vivo Toxicology Studies
A significant portion of the work performed in recent years has focused on inhalable formulations aimed at cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, and other indications, such as diabetes. Our team of scientists can conduct inhalation toxicity studies for inhaled products in both rodents and nonrodents. Test formulations can be either dry powder, solution/suspensions, or delivered through metered dose inhalers, though all materials require conversion into a respiratory exposure atmosphere. Our specialists have experience working with sponsors to ensure that their compound is properly aerosolized, regardless of the formulation.
With an (agro)chemical or inhaled drug, exposure may occur only once (acute single-dose toxicity or TK studies) or repeatedly up to two years, (when carcinogenicity is the endpoint). Other study designs include a comprehensive portfolio of developmental and reproductive toxicology (DART) studies, as well as neonatal and juvenile toxicology in various species and safety pharmacology.
Safety Assessment Products & Services
In preparation for a study, we assist with size reduction of test items (TI). The industry standard approach of producing test items suitable for inhalation studies is micronization/jet milling, but we offer several media milling options for size reduction.
Powder formulation can be prepared on site for use in GLP toxicology studies. Micronized test articles can be blended with an appropriate excipient, and the uniformity of the resultant blend and achieved concentration is determined. Results are then processed, verified, and audited by our QA unit, and a certificate of use prepared, allowing the blend to be released for use on the study.
Physicochemical analysis will improve the speed, quality, and rigor of the pre-dosing characterization work to develop a viable aerosol process. To troubleshoot and mitigate risk, Charles River offers a wide range of capabilities, including cover structural, chemical composition, visual/microscopy, thermodynamic, reaction/interaction, and sorption analysis-based techniques.
The Immunology Group provides guidance and assays as per ICHS8 to support immunotoxicology evaluation of compounds. In addition, we have conducted numerous assays to assess immunomodulation, such as measurement of immune biomarkers including cytokines, chemokines, complement factors, and immunoglobulins. We also support other immunogenicity testing needs, including screening, confirmatory assays, titration, and neutralizing antibody assays. Depending on the pharmacology and toxicology of the compound to be tested, it is possible that inhalation studies may have one or more of these assessments and assays included.
Our bioanalysis groups perform high-throughput non-GLP research-grade assays to assist in lead candidate selection and develop and validate quantitative bioanalytical assays from first principles or by method transfer from a client’s laboratory. We also validate assays in full compliance with GLP and other internationally recognized regulatory guidelines. These methods are then applied to determine the concentrations of specific compounds and/or metabolites in a range of biological matrices. Compounds routinely analyzed range from small new chemical entities (NCEs) to large macromolecules. To assist in bioanalysis, our Chemical Synthesis Group can produce nonlabeled or stable-labeled compounds for use as internal standards. We also accept sample deliveries for analysis as a stand-alone service.
Services provided include clinical chemistry, hematology, coagulation assays and urinalysis performed by experienced technical, scientific and biomedical staff. For inhalation studies, bronchoalveolar lavage analysis can be performed with cell count and other evaluations.
The resultant slides from inhalation studies prepared by the Histology Group are evaluated by in-house pathologists who participate in peer reviews and pathology working groups, and several of whom specialize in inhalation toxicology. Not only can digital microphotography be included in the contributing pathology report, but we are also able to share digitalized images of glass slides (for illustrative purposes) directly with the sponsor through the use of the Aperio system.
Laboratory Support Products & Services
We offer full-service support across the entire drug discovery and development continuum, including many products and services not specific to therapeutic area or indication.
Serving the needs of both small and large molecule developers, we offer a broad range of standard and specialized laboratory services to complement and enhance drug development programs, from discovery through safety and clinical trials. From complete IND-enabling programs to stand-alone assessments, our Safety Assessment team provides a full range of in vivo and in vitro testing services that comply with worldwide regulatory restrictions for the preclinical development of pharmaceuticals.
We provide a comprehensive range of testing programs and equipment to support pharmaceutical development. Our biologics testing solutions and portfolio of microbial quality control systems and services help clients ensure the safety, quality and compliance of their products. We support large molecule manufacturing from early preclinical formulation development through clinical and commercial manufacturing and release.
Exceptional support of the entire drug discovery and development process is a Charles River hallmark. As a customer-focused organization committed to advancing science and helping clients reach their goals, we continually strive to develop solutions that extend our support of their efforts. Because our industry-seasoned professionals have followed the same journey as our clients, we can provide insight into the bigger picture, advice on best practices, skilled staff to extend resources and targeted training to meet the unique challenges they face along the way.