EA808

Rat PK

This screening assay is used to determine the bioavailability/exposure of test compounds after two routes of administration to male rats.

Required from Customer

  • Test compound in powder form or preformulated
  • Dose routes—any two routes, including intravenous bolus (IV), oral gavage (OG), subcutaneous (SQ), and intraperitoneal (IP)
  • Dose (mg/kg) of test compound
  • Molecular mass (exact mass) of each test compound and its salt form
  • MSDS or handling and storage information, e.g., light sensitive, store at -20°C, etc.
  • If applicable, instructions for dose vehicle preparation

Deliverables

  • In-life observations on each rat
  • A table containing test compound concentrations in plasma samples at each time point
  • A table listing relative exposure (bioavailability) based on the  AUC for each compound and Concentration vs. Time profiles
  • A table containing appropriate pharmacokinetic parameters for each dose route: Cmax and Tmax for each compound, and half life, clearance, and volume of distribution of each compound after IV administration, if applicable

Substrate

  • Test compound in an appropriate dosing vehicle either individually or as a pool of compounds (cassette dose)

Assay System

  • Conscious, fasted, male Sprague-Dawley rats weighing between 200 and 400 grams; water is offered ad libitum

Assay Conditions

  • Three rats (N=3) per dose route
  • Sample blood from the jugular vein at the following time points:
    • Typically predose, 5 (IV), 15, 30 min, 1, 3, and 6 hours
  • Prepare plasma from each sample and freeze
  • Determine the concentrations of test compounds in dosing solution and incurred samples using a generic LC-MS/MS method with a minimum 6 point calibration curve*
    • For cassette dosing, one analytical method will be developed to include all compounds (if feasible) and one single injection will be used to quantify all test compounds
  • Non-compartmental analysis is used to determine PK parameters for each test compound

Assay QC

  • At least 60% of the calibration standards must be within ±20% of the theoretical values to accept the analytical run

Notes

  1. The results from this study are provided to the customer in the ExpressPlus report format, which may include graphical representations of data and comparison with historical data for reference compounds.
  2. *The analytical rigor does not include a pre-study validation, and QCs will not be used for sample analysis.
  3. Cassette dosing is a rapid and lower cost method for screening the pharmacokinetics of drug discovery candidates. However, interpretation of cassette dosing results can be confounded by drug-drug interactions among the discovery candidates.
  4. Mass of each test article must differ by at least 5 amu if cassette dosed—up to 5 compounds can be dosed in a single cassette—whether this is effective depends upon the compounds.
  5. Price for cassette dosing is for one analytical method and one single injection for quantification of all analytes.
  6. The plasma from rats dosed with different test compounds is pooled for analysis—whether this is effective depends upon the compounds.
  7. If required, Absorption Systems can determine a suitable dosing vehicle and prepare it for the experiment. Alternatively, Absorption Systems can prepare the dosing vehicle if the customer provides instructions.
  8. One hour formulation prep cost has been included in the study price. Additional time required for formulation preparation will be charged.
  9. Dose vehicle development is not included as part of this assay.
  10. The standard anticoagulant is sodium heparin. The customer can specify that another anticoagulant be used.

Options

  1. The customer must specify:
    • any two dose routes—IV, OG, IP, or SC
    • individual vs. cassette dosing
    • the dose (mg/kg) of each dose route
    • the formulation instructions, if applicable
  2. The customer can request:
    • the number of replicates (typically 3)
    • different time points and an extended duration
    • that Absorption Systems determine a suitable dosing vehicle
    • that Absorption Systems prepare the dosing vehicle using the customer’s instructions

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