Study Purpose
An ideal drug needs to have an appropriate dosage and dosing regimen to obtain the application advantages of clinical studies and commercial success. An optimal oral drug requires suitable solubility, mainly assessed by passive diffusion absorption, high bioavailability, multiple metabolic elimination pathways, and adequate safety windows. Candidate compounds are obtained by providing appropriate drug metabolism and pharmacokinetics (DMPK) screening methods and evaluation strategies in the drug design, screening, and optimization stages that establishes a quantitative structure-property relationship (QSPR) which optimizes the compound properties in terms of absorption, distribution, metabolism, and excretion (ADME), and provides the basis for subsequent clinical trials by establishing an in vivo-in vitro correlation model. In the early phase of drug discovery, high-throughput in vitro screening has the advantages of being fast and low cost. With drug research development, it is necessary to carry out in vivo experiments to evaluate the absorption, distribution, metabolism, and excretion characteristics of candidate compounds. Many pharmaceutical companies and research institutions increasingly favor rodent PK studies for their easy-to-build in vivo-in vitro relationship, lower demand for compounds, shorter TAT at a lower cost, diverse animal models, and mature in vivotechnologies. There are many types of rodent PK projects that can meet new drug discovery and development needs in each stage of preclinical new drug development and provide reference and guidance for extensive rodent PK experiments, pharmacodynamics experiments, and toxicology experiments.
Facilities Introduction
The rodent barrier facilities of WuXi AppTec DMPK are located in Shanghai, Suzhou, Nanjing and New Jersey, respectively. All facilities are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International). In addition, animal facilities in Shanghai and Suzhou have PHS Animal Welfare Assurance, and animal facility in New Jersey has OLAW assurance. The DMPK barrier facility can house more than 10,000 rodents, including rats, mice, guinea pigs, and hamsters.
Animal facilities have rodent surgical suites that distinguish surgical, preoperative, intraoperative, and postoperative areas. They also have a professional design to ensure efficient and high-quality surgery and perioperative care.
The facility environment is controlled with advanced electronic systems and monitored in real-time to ensure the environmental conditions meet global standards. A two-corridor design in this animal facility can minimize cross-contamination. The peripheral auxiliary area has a cage washing room and a special feed bedding storage room. The cage washing room is equipped with an international top brand automatic cage washer to ensure the highest level of cage sanitation.
The facility has an independent Institutional Animal Care and Use Committee (IACUC), veterinary care unit and engineering team to ensure the health and welfare of animals.
Assay Type
From Early Screening to IND Submission
·
Hit to lead
Fast PK: Rat and mouse PK (oral or intravenous administration)Targeted PK experiment: For example, study on the central nervous system and brain/plasma ratio determinationRoutine PK experiments: Study-specific disease model based on PK results and exposure-based Proof of Concept (POC) model testing
Lead optimization
PK study in rats and mice (administered through oral, intravenous, subcutaneous, intramuscular, and intraperitoneal routes. Species selection can be consistent with toxicology and efficacy studies) Single or multiple dosesExposure studies with different formulationCollection of different biological samples, such as cerebrospinal fluid, urine, and fecesTissue distribution validation studies, specific tissues can be collected such as brain, heart, liver, and lung
Preclinical candidate (PCC)
Single-dose or multiple-dose experiment following specific administration routePK experiments with different salt forms or crystal formsPK experiments with different dosage forms, including bridging studies with clinical formulationsTissue distribution study: Multiple tissues can be collected, such as the heart, liver, spleen, lung, kidney, small intestine, large intestine, muscle, and fatExcretion study: Biological samples collection such as bile, feces, and urineMaximum tolerated dose experiment (MTD) and dose escalation experiment
Investigational New Drug (IND) application
PK studies of single-dose and single intravenous administration (both rodents and non-rodents, at least three females and three males)Oral administration PK studies with high, medium, and low doses (rodents and non-rodents, at least three females and three males for each dose group)PK studies of medium dose and multiple oral administration (rodents and non-rodents, at least three females and three males)Tissue distribution studies after a single oral administration (at least three females and three male rodents at each time point, typically setting five time points, and no less than 13 tissues can be taken; tissue distribution isotope experiment - if needed)Biliary excretion studies with medium dose and single oral administration (rodent or non-rodent, at least three females and three males)Urine and fecal excretion studies with medium dose and oral administration (rodent or non-rodent, at least three female and three male, isotope excretion and mass balance study - as appropriate)Identify major metabolites in plasma and excretion (rodent or non-rodent, isotope identification of metabolites in plasma and excreta - if needed)Animal Species
Some Animal Species and Strains/Stocks
Mouse
ICR (CD-1)
C57BL/6
BALB/c
FVB
DBA/1
DBA/2
SJL
129
BALB/c Nude
Nu/Nu nude
CD-1 Nude
CB-17 SCID
SCID Beige
NOD SCID
OB Mouse
DB Mouse
P-gp/BCRP KO Mouse
Rat
Sprague Dawley
Wistar Han
Wistar
Brown Norway
F344 (CDF)
Lewis
Hamster
LVG Golden Syrian Hamster
Guinea Pig
Harley Guinea Pig
Route of Administration
Drug administration is one of the crucial parts of the in vivo study. It is essential to select the appropriate drug administration route in the early and late stages of drug development. Our team has developed more than 30 routes of administration based on customer needs and market foresight and provides high-quality rodent in vivo PK services to thousands of customers worldwide. This team has also established many unique technical capabilities, such as intravenous infusion for more than seven consecutive days. The team has launched many high-quality administration technologies for the respiratory system, ophthalmology, and nervous system and provided many trouble-shooting solutions for customer projects. The team's biggest dosing technical competencies are listed in the table below:
Team's Major Dosing Technical Capabilities
Case Sharing of Classic Administration Route
In Vitro Permeation Test (IVPT)
The transdermal drug delivery system (TDDS) has always been an attractive field as it can provide a therapeutic window larger than whole-body delivery. Topical skin formulations are widely used for topical administration, exert local effects, and cause systemic effects through skin absorption. Methods of evaluating topical drug transdermal delivery are divided into in vivo and in vitro [1]. Skin absorption is mainly a passive diffusion process. Literature has proven that the data obtained from in vitro studies complying with the appropriate protocol are of great reference values. Compared with traditional in vivoexperiments, in vitro methods can measure the drug concentration retained in the skin and the amount that diffused through the skin into the receptor chamber. This method allows the exploration of skin permeability at the early screening stage. No live animals are used in this study, and multiple replicates can be applied at the same or different compounds. This feature is especially suitable for comparing the skin penetration of the same compounds in various In Vivo studies complying with the appropriate protocol are of great reference values. Compared with traditional in vitro formulations and screening the transdermal properties of different compounds [2].
In Vitro Model for Investigating Drug Penetration
Research Data
In vitro , transdermal experiments tested the drug permeability of different batches of drugs using Bama minipigs’ skin. The data showed no significant difference in the in vitro permeation characteristics between the test and the reference.
Surgical Models
Partial Surgical Models
Case sharing of CMC surgical model
in situ single-pass intestinal perfusion (SPIP) model
To date, the most used model for predicting the absorption process in humans is the Caco-2 cell monolayer system. While drug permeability correlates well with drug absorption in humans and the Caco-2 studies, there are many limitations when studying carrier-mediated transport or monitoring intestinal metabolites [4]. in situ single-pass intestinal perfusion (SPIP) is the closest experimental method that mimics oral administration and directly measures compound absorption rate. The intestinal structure is similar in both humans and rodents, and there is a strong correlation between effective permeability (Peff) and fraction absorbed (Fa) between these two species (R2 = 0.8 to 0.95). It is easy to control the intestinal environment in SPIP studies, such as drug concentration in the perfusate, perfusate pH, perfusion flow rate, and target intestine perfusion part of the study. More importantly, the SPIP enables simultaneous measurement of the effective permeability (Peff) and flux of drugs appearing in mesenteric blood (Pb) [5, 6]. The team can use SPIP models in rodents to assess the intestinal permeability of test compounds and monitor their metabolites.
Validation Studies
Results of Validation Studies
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