Testing of compounds in mouse pharmacokinetic experiments

SOURCES SOUGHT NOTICE

1. Solicitation Number: 75N95019Q00323

2. Title: Testing of compounds in mouse pharmacokinetic experiments

3. Classification Code: 99

4. NAICS Code: 541380 Testing Laboratories

5. Description:
This is a Sources Sought notice. This is NOT a solicitation for proposals, proposal abstracts, or quotations. The purpose of this notice is to obtain information regarding the availability and capability of all qualified sources to perform a potential requirement.

This notice is issued to help determine the availability of qualified companies technically capable of meeting the Government requirement and to determine the method of acquisition. It is not to be construed as a commitment by the Government to issue a solicitation or ultimately award a contract. Responses will not be considered as proposals or quotes. No award will be made as a result of this notice. The Government will NOT be responsible for any costs incurred by the respondents to this notice. This notice is strictly for research and information purposes only.

Background: The National Institutes of Health (NIH) is the nation's leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability, conducting, supporting and making medical discoveries that improve people's health and save lives. The National Center for Advancing Translational Sciences (NCATS) is a translational science center that prides itself on its productive pipeline and is innovative in several ways. NCATS brings together a diverse range of scientists, including medicinal chemists, biologists, toxicologists, and engineers, to ultimately translate basic science into real products and services that help improve people's lives. Included in this process is the development of unique small molecules as potential anticancer agents.

Prior work at NCATS has produced a series of small molecule inhibitors, including NCGC00371481 and its structural analogs. Compounds such as '1481 have shown promising results in cellular and mouse models of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Further optimization of the biochemical, physiochemical and pharmacokinetic properties of these compounds is required, and may eventually produce a clinical candidate that could be used to treat cancers such as MDS and / or AML.

Purpose and Objectives: For a candidate compound to advance into clinical trials, it must display a wide range of acceptable properties. For this program, a potential clinical candidate must display potent inhibition of the desired targets. It must also display suitable pharmacokinetic (PK) properties in a range of preclinical species, including at least one rodent species (mouse or rat), as well as at least one higher preclinical species (dog or monkey). Good PK profiles in these species are required 1) to build models that predict good pharmacokinetic properties in humans, and 2) so that compounds can be given at high doses and high plasma exposure levels in preclinical safety studies.
To characterize and optimize the pharmacokinetic properties of our compounds in mice, we need to run a series of mouse pharmacokinetic experiments. Testing a set of 11 small molecule compounds in mouse PK experiments will provide critical data that identify the strengths and weaknesses of our current compounds' PK profiles and will help us optimize those profiles so that we can identify a suitable candidate for clinical trials.
For a given compound, pharmacokinetic properties may vary considerably across species. That is, properties in mouse, rat, dog, monkey or humans may vary. Preclinical drug discovery programs that want to advance compounds into human clinical trials ultimately need to test pharmacokinetics in mouse, rat, dog, and monkey prior to human testing. To maintain consistency, we prefer to run our mouse pharmacokinetic experiments using a vendor who can also provide future pharmacokinetic testing in rat, dog, and monkey.

Project requirements:
1. Test each of 11 small molecule compounds in mouse pharmacokinetic studies comprised of two dosing arms (one oral, one IV, n = 3 mice per arm).
2. Provide a comprehensive report for each of the 11 compounds detailing results from the pharmacokinetic experiment as described below in the Specific Requirements section.

Specific Requirements
1. Contractor will run the assays using scientists that have significant experience (>5 years) in the testing of small molecule compounds in mouse pharmacokinetic experiments.
2. Contractor will have significant experience (>5 years) in running mouse pharmacokinetic experiments.
3. Contractor must offer the option of follow-up pharmacokinetic testing in rat, dog, and monkey. This will allow continuity of service, and an 'apples-to-apples' comparison of pharmacokinetic data across all species.
4. Contractor will test compounds in mouse pharmacokinetic studies comprised of two dosing arms (one oral, one IV, n = 3 mice per arm). Test compounds will be administered as a single dose (either oral or IV, depending on the study arm), and in each study arm, 7 serial blood draws will be taken at 7 different time points covering a range of at least 8 hours post-dose. Plasma samples will be analyzed by LCMS to determine the concentration of test compound at each time point. That data will be used to construct a plot of test compound concentration in plasma vs. time for each dosing arm. A final report will be issued that contains these plots, as well as the calculated oral bioavailability (F%), clearance rate (Clp), half-life (t1/2), area under the curve (AUC), maximal concentration (Cmax), and volume of distribution (Vd) for the compound. The report should list the formulation used for dosing and should include a table of raw data showing the plasma concentration of test compound at each time point in each mouse, as well as the average or mean concentration across all 3 mice, and the standard deviation or standard error for each mean value.
5. Contractor will have access to all critical instrumentation necessary for this statement of work.
6. Contractor will be capable of testing the aforementioned 11 compounds in all the assays described above in.