This order provides for testing of 8 small molecule compounds in rat pharmacokinetic studies. These compounds are drug molecules being evaluated for a kinase inhibitor program. Testing of the compounds for their pharmacokinetic properties in rat will provide critical information on compound clearance, exposure, and bioavailability.
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 a number of ways. NCATS brings together a diverse range of scientists, including medicinal chemists, biologists, toxicologists, and engineers, in order 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.
In order 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) in order 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.
In order to characterize and optimize the pharmacokinetic properties of our compounds in rat, we need to run a series of rat pharmacokinetic experiments. Testing a set of 8 small molecule compounds in rat PK studies 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.
1. Test each of 8 small molecule compounds in rat pharmacokinetic studies comprised of two dosing arms (one oral, one IV, n = 3 rats per arm). Test compounds will be administered as a single doses (either oral or IV, depending on the study arm), and in each study arm, 8 serial blood draws will be taken at 8 different time points covering a range of at least 8 hours, and up to 24 hours, post-dose. Plasma samples will be analyzed by LCMS to determine the concentration of test compound at each time point.
2. Provide a comprehensive report for each of the 8 compounds detailing results from the pharmacokinetic experiment. The report must contain the following:
-A graphical plot of plasma concentration of test compound vs. time
-A table of raw data showing the plasma concentration of test compound at each time point in each rat, as well as the average or mean concentration across all 3 rats, and the standard deviation or standard error for each mean value.
-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.
3. Contractor will run the assays using scientists that have significant experience (>3 years) in the testing of small molecule compounds in rat pharmacokinetic experiments.
4. Contractor will have significant experience (>3 years) in running rat pharmacokinetic experiments.
ARTICLE H.40. CARE OF LIVE VERTEBRATE ANIMALS, HHSAR 352.270-5(b) (December 2015)
a. Before undertaking performance of any contract involving animal-related activities where the species is regulated by the United Sates Department of Agriculture (USDA), the Contractor shall register with the Secretary of Agriculture of the United States in accordance with 7 U.S.C. 2136 and 9 CFR 2.25 through 2.28. The Contractor shall furnish evidence of the registration to the Contracting Officer.
b. The Contractor shall acquire vertebrate animals used in research from a dealer licensed by the Secretary of Agriculture under 7 U.S.C. 2133 and 9 CFR 2.1 2.11, or from a source that is exempt from licensing under those sections.
c. The Contractor agrees that the care, use, and intended use of any live vertebrate animals in the performance of this contract shall conform with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (PHS Policy), the current Animal Welfare Assurance (Assurance), the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, DC) and the pertinent laws and regulations of the United States Department of Agriculture (see 7 U.S.C. 2131 et seq. and 9 CFR subchapter A, Parts 1-4). In case of conflict between standards, the more stringent standard shall govern.
d. If at any time during performance of this contract, the Contracting Officer determines, in consultation with the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health (NIH), that the Contractor is not in compliance with any of the requirements and standards stated in paragraphs (a) through (c)above, the Contracting Officer may immediately suspend, in whole or in part, work and further payments under this contract until the Contractor corrects the noncompliance. Notice of the suspension may be communicated by telephone and confirmed in writing. If the Contractor fails to complete corrective action within the period of time designated in the Contracting Officer written notice of
suspension, the Contracting Officer may, in consultation with OLAW, NIH, terminate this contract in whole or in part, and the Contractor's name may be removed from the list of those contractors with Animal Welfare Assurances.
Note : The Contractor may request registration of its facility and a current listing of licensed dealers from the Regional Office of the Animal and Plant Health Inspection Service (APHIS), USDA, for the region in which its research facility is located. The location of the appropriate APHIS Regional Office, as well as information concerning this program may be obtained by contacting the Animal Care Staff, USDA/APHIS, 4700 River Road, Riverdale, Maryland 20737 (Email: email@example.com
; Web site: ( http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare
(End of clause)
****(USE BELOW IN ALL SOLICITATIONS AND CONTRACTS INVOLVING LIVE VERTEBRATE ANIMALS.
ADDITIONAL INFORMATION TO COMPLETE THIS ITEM:
• Second paragraph: Insert the date of the contractor's Vertebrate Animal Section (VAS) from the technical proposal, as applicable. For additional information about the VAS, see NIH Notice NOT-OD-16-006 available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-006.html
ARTICLE H.41. ANIMAL WELFARE
All research involving live, vertebrate animals shall be conducted in accordance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy). The PHS Policy can be accessed at: http://grants1.nih.gov/grants/olaw/references/phspol.htm
In addition, the research involving live vertebrate animals shall be conducted in accordance with the description set forth in the Vertebrate Animal Section (VAS) of the contractor's technical proposal, as modified in the Final Proposal Revision (FPR), dated , which is incorporated by reference.
****(USE BELOW AS REQUIRED.
ADDITIONAL INFORMATION ABOUT THIS ITEM:
1. First sentence: Insert the appropriate I/C and contract number in each text box.
2. Fifth sentence: Insert the appropriate I/C in the text box.)****
ARTICLE H.42. INTRODUCTION OF RODENTS AND RODENT PRODUCTS
No rodent or rodent product shall be delivered into the NIH, environment (NIH) directly, or through collaborative research or holding facilities under contract to except by permit. Direct shipments to NIH from a Division of Veterinary Resources (DVR), Office of Research Services (ORS) approved source will be considered exempt. Non-exempt sources must be approved by permit issued through the DVR, ORS. The permit must be obtained by the Contractor prior to the shipment to NIH of the rodents and/or rodent products. The Contractor must be sure that this permit exists and is current before transferring rodents or rodent products into the NIH, environment. Refusal or negligence to do so will be considered a material breach of contract and may be treated as any other such material breach. Applications for permits should be submitted by facsimile not less than 30 days prior (60 days in situations where quarantine is likely) to shipping date to: NIH Division of Veterinary Resources (DVR), Office of Research Services (ORS), Building 14G, Service Rd. South, Room 102, BETHESDA MD 20892-5210, (301)496-2527, FAX: (301) 402-0352.
****(USEBELOW, IN SOLICITATIONS THAT INVOLVE LIVE VERTEBRATE ANIMALS.)****
1. Notice to Offerors of Requirement for Compliance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals, HHSAR 352.270-5(a) (December 2015)
The Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (PHS Policy) establishes a number of requirements for research activities involving animals. Before awarding a contract to an offeror, the organization shall file, with the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health
(NIH), a written Animal Welfare Assurance (Assurance) which commits the organization to comply with the provisions of the PHS Policy, the Animal Welfare Act, and the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, DC). In accordance with the PHS Policy, offerors must establish an Institutional Animal Care and Use Committee (IACUC), qualified through the experience and expertise of its members, to oversee the institution's animal program, facilities, and procedures. Offerors must provide verification of IACUC approval prior to receiving an award involving live vertebrate animals. No award involving the use of animals shall be made unless OLAW approves the Assurance and verification of IACUC approval for the proposed animal activities has been provided to the Contracting Officer. Prior to award, the Contracting Officer will notify Contractor(s) selected for projects involving live vertebrate animals of the Assurance and verification of IACUC approval requirement. The Contracting Officer will request that OLAW negotiate an acceptable Assurance with those Contractor(s) and request verification of IACUC approval. For further information, contact OLAW at NIH, 6705 Rockledge Drive, RKL1, Suite 360, MSC 7982 Bethesda, Maryland 20892-7982 (Email: firstname.lastname@example.org
; Phone: 301-496-7163).
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