Study Purpose
In the early stage of new drug discovery and development, target validation, lead discovery, and lead optimization are the main focus points. The experimental content primarily includes in vivo PK studies and tissue distribution studies. In the later stage, drug development selects a candidate molecule for clinical development and the Investigational New Drug (IND) application. At the preclinical stage, especially for Investigational New Drug (IND) Application, the study is required to be conducted in two species, rodent and non-rodent (usually dog, monkey, or minipig) [9].
WuXi AppTec DMPK Service department has international standard facilities that can hold thousands of high-level large laboratory animals. Our experienced and dedicated team with professional staff is committed to providing better experimental techniques and surgical skills applied during large animal studies. Furthermore, a close corporation with researchers from Bioanalysis & Formulation team help us simplify the regulatory guidelines and quickly obtain a wide variety of PK assays when a compound is administered to a non-rodent. We will also provide reliable data for evaluating the dose level for a compound in pharmacodynamics, toxicology and preclinical pharmacology.
Facilities Introduction
The large animal research facilities located in Suzhou, Nanjing and Nantong have Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC International) accreditation. The facility in Suzhou also has an Office of Laboratory Animal Welfare (OLAW)-approved Animal Welfare Assurance that is required by the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals.
Animal facilities are equipped with separate surgical areas, dissection rooms, and cage washing rooms, with human and logistic routes available, which can effectively minimize the risk of cross-contamination. To reduce cross-contamination, we have different personnel and logistics flow directions and independent rooms for Veterinary Care, Necropsy, Cagewash, and Animal Housing. The Cage Washer Room is equipped with automatic cage washers to achieve the highest degree of sanitation. Chips and intelligent cage cards are utilized to manage large animals, enhancing efficiency and quality management.
WuXi AppTec has an Institutional Animal Care and Use Committee (IACUC) to ensure that the in vivo research program complies with applicable laws, regulations, policies, and guidelines. The Engineering Department, Veterinarian Team, and Husbandry Team ensure our facility complies with Guide for the Care and Use of Laboratory Animals (Guide) requirements and provides good animal welfare, management, and maintenance of facilities. Records are carefully archived to ensure efficient data retrieval for each animal.
The animal facility is equipped with a HEPA-filtered and HVAC system. WebCTRL environment control system is applied to monitor the temperature, relative humidity, and pressure difference within the animal rooms. 12-hour light/dark cycles are automatically controlled for animal holding rooms. These environmental parameters meet international standards, including Chinese, American, and European standards. Moreover, animal environment enrichments, including toys, fruits, music, and TV are also provided for different species to maintain their physiological and psychological health.
We also have a professional and experienced Preclinical Formulation Team with advanced pharmaceutical preparation and detection equipment to improve our quality control. Equipment includes but is not limited to a Polarizing Microscope, Mastersizer 3000 laser diffraction particle size analyzer, NanoDrop One Spectrophotometer, and Retsch Planetary ball mill PM100, Waters HPLC.
Assay Type
From Early Screening to IND Submission
·
Hit to lead
Quick screening: e.g., PK study, oral dosing or intravenous administration in dogs or monkeys
Lead optimization
PK study in dogs or monkeys (oral/intravenous/subcutaneous/intramuscular/intraperitoneal administration; the species is consistent with that used in Toxicology studies and Pharmacodynamics Studies)Single-dose or multiple-dose studiesAUC (area under the curve) studies of different dosage formsStudies are required to collect different biological sample matrices, such as cerebrospinal fluid, urine, feces, etc.Tissue distribution studies are required to collect specific target tissues, such as the brain, heart, liver, and lung
Preclinical candidate (PCC)
Single-dose or multiple-dose in a particular administration routePK studies for the selection of different salt forms or crystal formsPK studies with various dosage forms, e.g., Formulation Bridge Study applied for Phase ITissue distribution studies are required to collect other tissues, such as heart, liver, spleen, lung, kidney, small intestine, large intestine, muscle, and fatExcretion studies are required to collect bile, feces, and urine
Investigational New Drug (IND) application
PK Study: single-dose via intravenous administration (at least three females and three males)PK Study: single oral administration of high, middle, and low dose levels (at least three females and three males for each dose level)PK Study: multiple oral administration of middle dose level (at least three females and three males)Biliary Excretion Study: single oral administration of middle dose level (at least three females and three males for each dose level)Urinary and Fecal Excretion Study: single oral administration of middle dose level (at least three females and three males)Identification of major metabolites in plasma and excreta (at least five)Animal Species
Large animal species and strain
Monkey
Cynomolgus macaques
Rhesus macaques
Ferret
Dog
Beagle
Pig
Bama mini-pig
Rabbit
New Zealand White
Chinchilla
Dutch-Belted
Japanese White
Route of Administration
Drug administration is a vital component of in vivo PK studies. Proper administration route selection is of great significance during early drug screening and late drug development. A variety of administration routes have been developed according to client demand and forward-looking marketplace strategies to provide high-quality In vivo PK Study service for thousands of clients worldwide. Specialized and high-quality skills and techniques include 72-hour continuous intravenous infusion in non-rodents without anesthesia, ocular administration, transdermal administration, and central nervous system (lateral cerebral, cisterna magna, intrathecal administration) administration. We constantly strive to provide better service and continuous improvement.
Team's Major Dosing Technical Capabilities
Maximum administrable volumes for different routes [10, 11, 12]
(ml/kg except where underlined- which is ml/site)
Case sharing
24 hour IV infusion
Historical data: 24hrs (30 mg/kg) IV infusion via femoralvein cannulation in cynomolgus monkeys (three males
and three females). Results are :
Surgical Models
Partial Surgical Models
Case sharing of CMC surgical model
Cisterna Magna Cannula (CMC)
For drugs acting directly on the central nervous system, accurate detection of drug concentration in the brain contributes to evaluate the ability of drugs towards the target site. Moreover, the direct measurement of drug concentration of Cerebrospinal Fluid (CSF) has more accuracy than using the concentration of free drug in plasma to predict the drug concentration in the brain [13] [14]. The drug concentration of CSF can be used as an effective indicator for evaluating drug exposure for those CNS (Central Nervous System) drugs and provide a basis for these drug candidates to move to the next stage.
We have established Cisterna Magna cannulation (CMC) models in monkeys and canines according to the literature [15] since 2009, which allows us to collect CSF samples consecutively without anesthesia to obtain relevant PK curves and evaluate the drug’s ability to cross the BBB (blood-brain barrier). The CMC model animal lasts up to 2 years, and we have standby CMC model animals for use anytime to shorten the leading time. Nearly 200 projects, including IND applications, were completed by 2020.
Validation Studies
Objective: To compare the stability of the CMC model in dogs with different surgery recovery times.
Methods: Lidocaine hydrochloride injection drug (25 mg/dog) was administered intravenously in 3 male beagle dogs five days, 14 days, 35 days, and 63 days after surgery. The plasma and CSF samples were collected at the same time point, and the results of drug concentration were as follows:
Conclusion: The data showed a slight deviation in drug concentration between the plasma and CSF matrix on postoperative days 5, 14, 35, and 63, indicating that our surgical model is reliable with consistent data.
List of biological sample collection of large animals
**Samples of various brain tissues include but are not limited to the caudate nucleus, cerebellum, cerebral cortex, white matter of the cerebrum, cingulate gyrus, cingulate sulcus, corpus callosum, external capsule, internal capsule, globus pallidus, hippocampus, hypothalamus, pituitary gland, midbrain, medulla oblongata, optic nerve, optic chiasm, pons, shell, and spinal cord.
*** Terminal Collection
List of Organ and Tissue Matrix for histopathology
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