This website stores cookies on your computer. These cookies are used to collect information about how you interact with our website and allow us to remember you. We use this information to improve and customize your browsing experience and for analytics and metrics about our visitors both on this website and other media. To find out more about the cookies we use, see our Privacy Policy.

LocationsNews & Updates

en

CN EN
Contact Us

What can we help you find?

Top Searches

PROTAC

ADC

RNA

ADME

OLIGO

Oligonucleotide Drugs DMPK Services

WuXi AppTec Service provides tailored and comprehensive DMPK evaluation specifically designed for different oligonucleotides (siRNAs, ASOs, AOC, etc.) to accelerate the Development & Application of Oligonucleotide drugs.

REQUEST A QUOTE
DOWNLOAD THE BROCHURE

  • Overview

  • Study Models and Platforms

  • Experience

  • Study Strategies and Assays

  • Instruments

  • Case Study

  • FAQs

  • Related Resources

  • Related Services

Novel Drug Modalities

Connect with us

Overview

Benefited from our extensive experience with oligonucleotide studies, combined with guidelines issued by various drug regulatory authorities, industry white papers and studies in frontier literatures, WuXi AppTec DMPK has established a set of pharmacokinetic evaluation system tailored for oligonucleotide drugs1,2. We can offer a comprehensive list of in vitro assays and in vivo PK experiment designs, and can conduct mass balance and tissue distribution studies with radioisotope labeling, provide diversified quantitative analysis methods for oligonucleotides, and possess the ability to identify metabolites. Our advantages in setting up preclinical PK strategy, data interpretation and cross-departmental cooperation, can effectively shorten the development cycle of oligonucleotide drugs. 

Learn More

Study Models and Platforms

  • Comprehensive capabilities with an integrated bioanalytical platform

    Pharmacokinetic/pharmacodynamic studies of oligonucleotides require a diverse array of bioanalytical platforms to support the measurement of plasma/tissue concentration, tissue distribution, concentration of oligonucleotide loaded into the RNA-induced silencing complexes (RISC), knockdown efficiency of targeted mRNAs and proteins. We have extensive experience and comprehensive instruments to provide a wide range of bioanalysis solutions for different types of oligonucleotides, from early-stage drug screening to IND-filing.

    H02_图12.jpg

  • In vitro ADME study platform

    Oligonucleotides can be metabolized by ubiquitous nucleases through the body. In vitro experiments to investigate the stability of oligonucleotides in blood, target tissues, and lysosomes/tritosomes can support the evaluation of their stability in the circulatory system and targeted organs, and help optimize their chemical modifications. Additionally, plasma protein binding results can assist in understanding their PK/PD relationship. WuXi AppTec DMPK has successfully established a variety of in vitro stability models for oligonucleotides, including plasma, serum, liver and kidney S9 and homogenates, hepatocytes, lysosomes and other matrices, also established PPB assay using different methods (ultrafiltration, ultracentrifugation and electrophoretic mobility shift sssay).

    31.676 28_anyaivanova121000017.jpg

  • In vivo PK studies of oligonucleotides

    Currently the most common systematic administration methods for oligonucleotides are intravenous and subcutaneous injection, while local administration methods include intrathecal administration, and intravitreal injection. Compared to conventional small molecules, the concentration of oligonucleotides in the target tissue (such as liver) has a much better correlation with the efficacy of oligonucleotides than the plasma concentration. WuXi AppTec DMPK can conduct in vivo PK, tissue distribution, excretion studies of oligonucleotides with different routes of administration in mice, rats, and monkeys. In particular, we had established a mature method of intrathecal injection of oligonucleotides with high a success rate, as well as liver biopsy techniques to support the PK studies of target tissues in monkeys.

    IN-Vivo.jpg

  • Oligonucleotide metabolite profiling and identification platform

    Well in vitro-in vivo correlation of metabolism experimental system, including different in vitro metabolic incubation systems, and in vivo plasma, targeted tissue and excreta metabolism studies. With flexible optimization of analytical conditions, our team of experienced scientists use both manual screening techniques and oligonucleotide-specific software (Thermo Scientific’s BioPharma Finder) to perform metabolite profiling and identification. We have the capability to run 100 + MetID studies each year for oligonucleotide, including a variety of ASOs and siRNAs with different chemical modifications and delivery systems.

    Oligo-MID.jpg
Start your study
Contact Us

Experience

  • 5+

    Years’ experience in oligonucleotide drug development

    E1_icon06.svg

  • 20+

    IND filing molecules

    E1_icon10.svg

  • 70+

    Global clients of oligonucleotides

    E1_icon07.svg

Study Strategies and Assays

  • There are various types of oligonucleotides, and their pharmacokinetic properties vary depending on mechanism, delivery system, and chemical modification. In the preclinical development stage, study strategies should be customized according to the specific characteristics of the oligonucleotide to accelerate its development. For in vitro ADME study, it is necessary to select an appropriate in vitro metabolic model based on the structural characteristics of the drug; for in vivo PK study, different administration methods can be used to investigate the PK properties. An appropriate detection method should be developed in accordance with the properties of the oligonucleotide.

    H02tu1-55.jpg


EXPLORATORY

Lead Molecule Optimization

PRE-CLINICAL

Support Clinical Candidate Molecule Characterization and IND Applications

CLINICAL

Support Clinical Development and NDA Applications

ADME

Plasma protein binding

S9 metabolic stability

Plasma/serum stability

Tissue homogenate metabolic stability

Lysosome/tritosome metabolic stability

Hepatocyte stability

Plasma/tissue homogenate/S9/hepatocyte metabolite identification and profiling

Plasma protein binding

Tissue homogenate metabolic stability

Plasma/serum stability

S9 metabolic stability and metabolite identification

ADME study with radiolabeled compounds in toxicological species

Identification of metabolites from in vivo samples (tissue, plasma, urine, feces, bile, cerebrospinal fluid, etc.)

Identification of metabolites in human plasma, urine, and feces, etc.

Identification of metabolites from in vivo samples such as tissue, plasma, urine, feces, and bile in toxicological species

DDI


Inhibition of drug transporters

CYP enzyme inhibition (reversible and time-dependent inhibition)

CYP450 enzyme induction

Prediction of DDI risks in human through PBPK modelling

Clinical DDI study

PK

Tissue distribution in rodents

Biomarker detection in PK or PD species

PK study and tissue distribution in rodents

Study on urine, feces, and bile excretion in rodents

PK study and tissue distribution in non-rodents

In vivo PK study

Immunogenicity evaluation

In vivo population PK study


Instruments

    • H02_图2.png

      Sciex Triple QuadTM 6500+

    • H02_图3.png

      Q-ExvtiveTM Plus

    • H02_图4.png

      Fluorescence Detectors

    • H02_图5.png

      Molecular Devices SpectraMax M5e

    • E1_图2.png

      QuantstudioTM 7 fLEX

Case Study

  • Integrated bioanalysis of GalNAc-conjugated siRNAs

    Background: Cemdisiran is an siRNA conjugated with N-acetylgalactosamine (GalNAc) with an asymmetrical RNA/dTdT overhang at the 3′ end of the AS. It targets the C5 complement pathway and treats complement-mediated diseases by inhibiting the hepatic production of C5 complement proteins.

    In vivo studies: We carried out a PK study in mice according to the conventional early in vivo PK protocol of siRNAs. Plasma, serum, and liver samples were collected and analyzed at multiple time points after a single administration by subcutaneous injection. The specific study design is shown in Figure 1: Three dose groups of low, medium, and high were set, and the mice were tranquilized to collect biological samples at 1 and 6 h and on days 1, 2, 3, 7, 14, and 21 after a single dose.

    H02_图7.png

    Figure 1. Cemdisiran mouse PK study design and bioanalytical solutions


    In this study, three different bioanalytical platforms and four bioanalytical methods were used to analyze the samples:

    (1) The plasma and liver concentrations of the siRNA were quantified using LC-MS/MS (Figure 2).

    (2) Levels of C5 complement protein in serum were detected using ELISA (Figure 3).

    (3) The RISC concentration in the liver was determined using RNA immunoprecipitation combined with stem-loop RT-qPCR.

    (4) Target gene expression levels were determined in the liver using stem-loop RT-qPCR.

    Results: By detecting the RISC concentration in liver tissue and comparing it with the inhibition rate of the target protein or the degradation rate of the target mRNA (Figure 4 and 5), it can be seen that the RISC concentration, rather than the drug concentration in free plasma, is more closely related to the gene silencing effect in target. We successfully applied suitable bioanalysis platforms to support the PK/PD studies of oligonucleotides.


    Learn More

    • Rectangle02.jpg

      Determination of the Cemdisiran concentration in the livers of mice in different dosage groups by LC-MS/MS

      Figure 2

    • Rectangle03.jpg

      Determination of C5 complement protein levels in serum using enzyme-linked immunosorbent assay (ELISA)

      Figure 3

    • Rectangle04.jpg

      RISC concentration in mouse liver vs. C5 complement protein inhibition rate

      Figure 4

    • Rectangle05.jpg

      RISC concentration in mouse liver vs. target gene mRNA degradation efficiency

      Figure 5

FAQs

  • What are oligonucleotide drugs？

    Oligonucleotides are synthetically modified nucleic acids that can modulate gene expression via a range of processes, which primarily include small interfering RNA (siRNA), antisense oligonucleotide (ASO), micro RNA (miRNA), and aptamer. They have the potential to target traditionally undruggable disease-causing genes and patient-specific sequences that are conducive to rare diseases.

  • What studies are recommended for the early DMPK evaluation of oligo molecules?

    The early DMPK evaluation of Oligo can be roughly divided into in vitro stability studies of different models and in vivo tissue distribution +PKPD studies in pharmacodynamic related species. It’s recommended to use platform-based approach for the oligo drug development. For well-established platform (such as GalNAc-siRNA) that already has more mature modification and delivery system, some studies can be postponed or only need to be characterized at the IND filing stage. For oligo with new chemical modifications or delivery platforms, in vitro stability experiments, metabolite identification, and PKPD experiments will have more significance to shed light on the lead optimization in the early stage.

  • How to select the animal species in the preclinical PK studies of oligo?

    Considering the gene homology reason and consistency of oligo’s metabolism across species, we can use either mouse or rat in rodent studies depending which one is more pharmacodynamically related, but most frequently select monkey in the large animal studies because their PK is more predictive of humans.

Related Resources

Browse All Oligonucleotide Resources

Related Services

References

  1. 1.

    Berman, C. L., Antonsson, M., Batkai, S., Bosgra, S., Chopda, G. R., Driessen, W., Foy, J., Hassan, C., Hu, X. S., Jang, H. G., Meena, Sanseverino, M., Thum, T., Wang, Y., Wild, M., & Wu, J. T. (2023). OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides. Nucleic acid therapeutics, 33(5), 287–305. https://doi.org/10.1089/nat.2023.0011

  2. 2.

    Guidance, D. Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics. Guidance for Industry. (2022)

View More

Stay Connected

Keep up with the latest news and insights.

  • Email address*

    * Please check the filled content

  • First name*

    * Please check the filled content

  • Last name*

    * Please check the filled content

  • Company*

    * Please check the filled content

By clicking submit, you consent to WuXi AppTec DMPK collecting and processing the information you provide for our internal purposes, in accordance with our privacy policy.

* Please agree to the Privacy Policy

Submit

Thanks for signing up

Help us get to know you better! By customizing your email preferences, we can deliver curated content relevant to you.