Pharmacokinetic Studies – PK Studies are key activities of early drug development. Our Pharmacokinetic screening (PK studies) can be exploratory, or can be more extensive. Understanding the pharmacokinetic properties (PK) of a test article is an essential component of drug discovery and development programs.
In Vivo PK screening can be instrumental in the selection of lead compounds with desirable bioavailability profiles for further investigation in drug development programs. Well-designed PK studies provide ADME (absorption, distribution, metabolism and elimination) data to assist in the study design and species selection of preclinical studies, including dosing schedule and dose levels. PK analysis prior to nonclinical toxicology studies verify that the formulation and dose form provides adequate drug exposure in the test animal.
GVK BIO conducts regular PK studies and can also customize it based the requirements of the clients. Pharmacokinetic PK Studies and toxicokinetic analyses are key activities of early drug development. Thoroughly understanding the DMPK of a potential clinical candidate can have a huge impact on the success of a drug discovery program.
PK and TK studies provide useful and required information that informs no effect levels (NOEL), human equivalent doses (HED), and pharmacokinetic/pharmacodynamic (PK/PD) drivers. Carrying out PK studies enables the determination of PK parameters such as AUC, clearance, volume of distribution, half-life, Cmax, and Cmin.
GVK BIO offers a comprehensive solution for non-GLP PK studies that includes quick turnaround PK screening for lead optimization or formulation evaluation, and full PK programs that encompass the in-life portion, bioanalysis and PK modeling. Studies can be conducted in rodents and nonrodents, including ferrets, dogs, mini pigs, and nonhuman primates (NHPs).
Bioanalysis is performed for determination of small molecules in blood, plasma, serum, CSF, or tissues. Our state of the art bioanalytical capabilities include LC-MS/MS – AB SCIEX 5500 and robotic sample prep systems. Biologic drugs may be determined using ELISA or qPCR assays.
In Vitro Metabolism
Characterize your compound’s ADME properties and potential drug interactions with an In Vitro assessment from our metabolism team. You get expert study design and data interpretation giving you specific insight to help in the development of your non-clinical and clinical strategy.
Drug-transporter interaction models
Select the best candidate and meet the latest expectations of regulatory agencies by assessing drug transporters key to drug disposition. Our widely published scientists coupled with expert analytical capabilities walk you down a path that helps you reach your drug development milestones with confidence.
Understand your compound’s absorption potential by assessing membrane permeability with our Caco-2 In Vitro absorption team. Caco-2 cell monolayers are an excellent model for assessing oral permeability and the investigation of absorption mechanisms involving P-gp and BCRP.
Plasma Protein Binding and Blood Cell Partitioning
Assess your compound’s distribution within animals or humans. Determine In Vitro and Ex Vivo protein binding and blood cell partitioning with our team who utilizes equilibrium dialysis, ultrafiltration and blood cell partitioning techniques.
Drug-drug interaction models
Get an early read on the drug-drug interaction potential of your candidate while minimizing the use of animals with our In Vitro and Ex Vivo metabolism assays. Our team routinely performs CYP450 induction, inhibition & identification, cross species comparison, and metabolite identification & profiling.
Determine the chemical reaction metabolizing your drug and identify the associated CYP enzyme to better predict and understand the potential for drug-drug interactions.
Establish the percentage of your compound’s metabolism over time using microsomes and/or hepatocytes. As your partner we will compare and assess your compound’s metabolic rate and metabolites generated across species to help you project human PK values.
Metabolite Identification and Profiling
Integrate your compound’s metabolite analysis across nonclinical and clinical study designs to improve your strategic methodology. With hundreds of metabolite identification assessments per year, our team of experts utilize the latest technology providing critical data to help you make informed decision faster.
Nonclinical PK Screening
Predict the metabolism and PK of your drug candidate in humans with flexible study designs incorporating in-life and/or analytical support. Our fast study starts, established in-house colonies and efficient study execution provide you a cost effective solution.
Rapid PK Screening
The iterative nature of in vivo PK screening requires rapid cycle times with changing priorities. We have built a team of experienced scientists with facilities and processes designed specifically to meet these challenging Pharmacokinetic Screening requirements.
From standard screening to more complex studies, our team of experienced team can also assist in designing the best strategy and protocols customized to suit any drug discovery program. Rapid study initiations facilitated by our maintenance supply of rodents and colonies of non-rodent species along with standardized protocols and fully integrated LC-MS/MS bioanalysis of PK samples, including small volume samples, result in better data faster
GVK BIO ensures safe and efficacious dosage regimens through the application of pharmacokinetic / pharmacodynamic principles and the determination of drug serum concentrations. The iterative nature of in vivo PK screening requires rapid cycle times with changing priorities.
Our Pharmacokinetic Services team conducts typical pharmacokinetic study which involves administering a fixed amount of the drug (the dose) to the subject (various animals) and at various times post dose, samples of an easily accessible tissue (usually blood/plasma) are drawn and collected for analysis of the drug
From standard screening to more complex PK studies, our team of experienced study directors can also assist in designing the best strategy and protocols customized to suit any drug discovery program.
In Vivo PK Studies
- Rank-ordering compounds/formulations
- Bioavailability and bioequivalence
- Dose proportionality (ascending dose)
- Dose linearity (multiple dose)
- Drug-drug interactions
- Special populations
- Tissue distribution (non-radioactive)
- Blood brain barrier
- Anti-drug antibodies
- Non-compartmental and compartmental pharmacokinetics
- Pharmacodynamic and pharmacokinetic modeling
- Input into study design, including preclinical-to-clinical considerations (allometric scaling and human equivalent dose projections)
Administration Routes and Collection
- Single agents, cassette dosing, single dose and repeat dose
- Dosing by PO, IV, IP, SC, etc.
- Serial sampling in all species
- Tissue, urine and CSF collection
- Bile collections by bile duct cannulation (BDC)
- Fully integrated bioanalysis services
- Bile duct cannulation
- Vascular access ports
- Portal vein cannulation
- Intestinal access ports
Pharmacokinetic Studies will include:
- Evaluating compounds in various formulations, both solution as well as suspension dosing in various species.
- Studying correlative aspects between the In Vitro and In Vivo metabolism of analogs to increase throughput and help lower cost.
- Dose escalation studies in rats or dogs with the potential for follow up in the 7- and 28-day tox studies in rats/dogs that would help plan for Phase I and in some cases Phase II clinical trials.
- Cassette (n-in-1) PK for early discovery compound screening and decision prioritization
- Drug distribution in tissue/organ and body fluid and determination of blood and brain ratio for brain penetration
- Metabolic kinetics with active metabolites
In order to provide a significant enhancement in speed and efficiency it becomes highly beneficial at GVK BIO to conduct both the in vivo PK quantification and identification of the major metabolites on a single instrument platform. provides our customers fast turnaround and close management of PK screening projects.
Rat PK Studies
This screening assay is used to determine the bioavailability of test compounds relative to a reference compound after oral administration to rats
Catalog number EA801
Customer Deliverables for PK Screening
- Test article in powder form or preformulated
- Dose of test article and reference compound—typically 10 mg/kg
- Molecular mass (exact mass) of each test article and its salt form
- MSDS or handling and storage information, e.g., light sensitive, store at -20°C, etc.
PK Screening Deliverables from GVK BIO
- In-life observation on each rat
- A table containing test compound concentration in plasma samples at each time point
- A table listing relative exposure (bioavailability) based on the AUC for each compound, Cmax and Tmax of each compound
- Half-life, volume of distribution, clearance after IV dosing
- An appendix containing the bioanalytical data
- Test compound dissolved in an appropriate dosing vehicle
Assay System used in our PK Screening
- Conscious, fasted, Sprague-Dawley rats weighing between 200 and 400 grams. Water is offered ad libitum to the rats
- Three rats (N=3) per dosing route group
- Sample blood from the jugular vein at timepoints specified by the customer
- Prepare plasma from each sample and freeze
- Determine the concentrations of test compound using a generic LC-MS/MS method with a minimum 6-point calibration curve
- Non-compartmental analysis is used to determine PK parameters for each test article
- Adverse reactions, if any, are reported to the customer
- Analytical data are accepted only when at least two-thirds of the analytical control samples and 60% of the standards used to create the calibration curve have a back calculated accuracy of ±15% (at LLOQ, ±20%)
- The amount of test compound required depends on the dose, i.e., mg of test compound per gram of rat, and the number of rats.
- The standard strain of rats is Sprague-Dawley. The customer can specify the use of other commercially available strains.
- GVK BIO can develop the dose vehicle for this the PK studies.
- The customer can elect to perform the bioanalysis while GVK BIO only does the dosing and sampling.
- The standard anticoagulant is sodium heparin. The customer can specify that another anticoagulant be used.
- A complete analytical method development includes:
- Optimization of MS: Initial conditions will be established by infusing a solution containing the test compound into an appropriate mass spectrometer. The goals in MS optimization are to maximize detector response for the test compound and determine the approximate lower limit of quantitation (LLOQ) of the test compound.
- Optimization of HPLC: HPLC parameters will be optimized using an appropriate selection of LC column(s) and mobile phase. The goal in HPLC optimization is to develop appropriate chromatographic run-times while maintaining adequate levels of sensitivity.
- Optimization of Sample Preparation: Various means of sample preparation, e.g., direct injection, dilution with appropriate solution, protein precipitation, solid phase extraction etc., will be evaluated for their efficiency in extracting the test compound from the biological matrix. The goal in extraction optimization is to achieve the required lower limit of quantitation (LLOQ) while alleviating matrix suppression effects.
- A pre-study validation is performed using calibration standards and quality control (QC) samples containing the test compound at known concentrations. In order for the analytical method to be considered acceptable the results from at least one method validation run must meet the following criteria:
- The standard curve must include a minimum of five standards with their concentration back calculated to ±15% (±20% at the LLOQ) of their nominal concentration when the correlation coefficient of the regression model is ≥0.990
- The calculated concentration of at least two-thirds of all QC samples and at least one-third of the QC replicates must fall with ±15% of their respective nominal concentration.
- The intra-assay coefficient of variation (CV) of the replicate determinations of the low, medium and high QC samples must not exceed ±15%, and the average concentration for each set of QC replicates as calculated using the standard curve must be within ±15% of their nominal concentration.
- The lowest standard is accepted as the lower limit of quantitation if the typical response at this concentration is at least 5 times greater than any interference in the blank matrix at the retention time of the analyte(s).
- The response ratio of any interfering peak(s) in the matrix blanks at the retention time of the analyte(s) must be < 20% of the response to the LLOQ standard
- The customer must specify:
• the use of either the standard or a custom report format
• the dose vehicle(s)
• the strain of rats
• the sampling time points the concentration for IV dosing
• the concentration for OG dosing
- The customer can request:
• a different anticoagulant be used
• that GVK BIO determine a suitable dosing vehicle
• that GVK BIO prepare the dosing vehicle using the customer’s instructions
• a more complete bioanalytical method validation, e.g., inter-day variability, and assessment of the stability of the samples
• that GVK BIO only dose and sample the rats (in-life only)
• that GVK BIO analyze the plasma collected by others
• that GVK BIO perform the PK analysis on data collected by others
GVK BIO Advantage
- Rapid turnaround from PK study initiation through generation of final report
- Highly experienced team of analytical chemists with more than 60% of the team holding advanced degrees
- Flexible, collaborative approach with customized study designs
That was the comprehensive list of our Pharmacokinetic screening services. Feel free to contact us regarding any query. Our PK Services team will get in touch with you as soon as possible.