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Toxicokinetic (TK) Analysis for Preclinical Drug Development

The main goal of preclinical toxicokinetic (TK) studies is to establish a correlation between a candidate compound’s concentration or dose and its potential toxicity.
 
TK studies are conducted during the drug development process as part of non-clinical toxicology or safety studies. Data obtained from the early non-GLP exploratory toxicology studies help a drug developer understand more about the compound before definitive (GLP) toxicology studies, and TK data from the definitive toxicology studies provide the detailed systemic exposure profile essential for dosing considerations prior to first-in-human (FIH) studies and other clinical phases. Data from an early TK study can also help to reduce the number of laboratory animals used in a drug’s development, aligning with international goals of the 3Rs (replacement, reduction and refinement) of animals used in research. 
 
In addition to our core in vivo ADME and radiolabeling services at the Drug Development Solutions Center, we can also offer analytical support for your in vivo toxicokinetic studies. Extensive experience, state-of-the-art instrumentation, and Good Laboratory Practices (GLP) certification for bioanalytical services enable the team in our Tokai facility to deliver reliable results.
 
Within the study of absorption, distribution, metabolism/biotransformation, and excretion (ADME), toxicokinetics analyzes the systemic exposure of study animals and the effects of xenobiotics in relation to dose level and time. This data can be used for:1, 2

  • Determination of toxicokinetic profile in toxicity studies
  • Selection of dose, form, and route
  • Toxicity evaluation
  • Toxicological mechanisms
  • Comparison between human and animals

TK Analysis at the Drug Development Solutions Center

Between the Drug Development Solutions Center’s superior analytical capabilities and an external partner specializing in animal toxicology to carry out the experiments, we can help you achieve high-quality, GLP-compliant toxicokinetic data. We have bioanalytical capabilities both in Tokai and in Kansas City for biological matrices of treated animals, and then specific TK parameters are defined using the latest version of WinNonlin at the Tokai facility.

The Drug Development Solutions Center has accumulated over 50 years’ experience performing radiolabeled (RI) experimentation, synthesis, and purity checks for pharmaceutical companies as the leading in vivo CRO in Japan. Their facilities are certified by AAALAC International to meet compliance with ethical requirements upheld by FDA, EMA, and PMDA for all animal studies, and GLP certified for all bioanalytical services.

After developing and validating the analytical methods for samples obtained in safety studies, the measurement of drug concentration in biological samples is conducted under international GLP standards. Data conversion service is also available, where TK data are presented in accordance with SEND (Standard for Exchange of Nonclinical Data required for submissions to FDA).

For large molecule drugs, a TK study can also provide data about the formation of anti-drug antibodies and their neutralizing properties to inform dosing considerations.

TK Analysis Features & Options

  • High-sensitivity determination of drug concentration in biological matrices from treated animals
  • Elucidation of metabolite profiles and structure via LC-MS/MS
  • Calculation of TK parameters using WinNonlin (v 8.1)
    • Specific parameters such as Cmax, Tmax, AUC, t1/2, clearance (CL), volume of distribution (VD), etc.
  • Microsampling options available with corresponding high-sensitivity analytical capabilities
  • Immunological methods and analysis 
    • Bead-based suspension array
    • ELISA

Regulatory Compliance

Toxicokinetic studies and follow up analyses are designed according to Japanese Pharmaceutical and Medical Devices Agency (PMDA) standards as well as recommendations described in most recent publications by international regulatory authorities, including the Guideline on Bioanalytical Method Validation in Pharmaceutical Development (Notification No. 0711-(1) of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health and Welfare, 2013) and the Good Laboratory Practice Standards for Non-clinical Safety Studies on Drugs (Ministry of Health and Welfare Ordinance No. 21, 1997).

While in the United States, there is no method by which an institution can claim certified compliance with GLP standards, the PMDA can grant certification to facilities in Japan following an inspection for GLP-compliance in specific practices. The Drug Development Solutions Center has this certification for all its in vivo bioanalytical services, including TK analysis.

Instrumentation Capabilities

We use only highly-sensitive analytical instruments and immunological techniques to accurately determine drug concentration for a TK service:

  • LC-MS/MS
    • QTRAP5500, QTRAP6500+
    • API5000
    • Xevo TQ-XS
  • Plate reader
    • Luminex (Bio-Plex 200 and Luminex100/200)
    • ECL (SECTOR Imager 6000)
    • Multi-label reader (Spectramax, EnVision, Mithras LB940-BA, PowerScan HT)
    • Digital ELISA (Simoa HD-1)

Learn More About

About the Authors

Madison (Knapp) Esely-Kohlman received her BS from the University of Missouri – Columbia and is currently SEKISUI XenoTech’s Marketing Communication Specialist, developing scientific content that communicates the value and expertise of internal contract service and test system production teams. Madison joined SEKISUI XenoTech as the Scientific Communications Coordinator in 2019 after serving in similar positions at CropLife America, Bond Life Sciences Center and the University of Missouri CAFNR Office of Communications.
Jolanta Golec has been with the SEKISUI Drug Development Solutions Center, our sister lab in Tokai, Japan, since 2013. She has experience serving in both scientific research and sales promotional capacities. Jolanta holds a M.Eng. in Agriculture from the University of Agriculture in Krakow (Poland), M.Sc. in Pharmaceutical Biotechnology from the University College Cork (Ireland) and is working on her MBA from the University of Manchester (UK).
Dr. Pallavi Limaye completed her Ph.D. in Toxicology from The University of Louisiana in 2004. Pallavi joined SEKISUI XenoTech in 2011 as a Research Scientist and served as a study director for in vitro drug metabolism studies. In 2013, she joined Xenometrics LLC, now a part of Charles River Laboratories, as a Senior Scientist and served as a study director for regulated nonclinical IND- and NDA-enabling toxicology studies. From 2018 to 2020 Pallavi worked at MRIGlobal as a Principal Scientist and oversaw nonclinical toxicology and animal health studies, as well as contributed to containment research with select chemical agents. She joined SEKISUI XenoTech’s consulting team in 2020 and provides input on drug-drug interaction study needs for sponsors. Pallavi has also published various articles and contributed many book chapters and is actively involved in scientific societies.

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