WA3FullMouse RatPK.pdf

RFP/N01-CM-07014-39

Attachment 22, WA 3

NCI CONTRACT WORK ASSIGNMENT

Contractor: To be filled in WA Title: Analytical method development with full validation and PK/bioavailability studies in mice and rats with a small molecule to be determined

Contract No: N01-CM-________ WA No: 3 Modification No: 0 WA Originator: Project Officer Contracted WA Area:

Date Prepared: ________________

Part I. INITIATOR'S REQUEST

A. Period of Performance: Month 3 thru Month 9 (7 months total)

B. WA Description:

Compound background summary would be provided here. Assume available information includes:

• Structure

• A measure of potency (e.g., NCI60 or other in vitro data)

• Any previously developed analytical methods (may be for neat compound only)

• Solubility and formulation information

• Dose ranges used in mouse xenograft studies (including route and schedule); single dose MTD not determined.

• Any other available relevant data

Specifically, the following tasks should be undertaken:

• Develop and validate a sensitive analytical method (most likely LC-MS/MS) for the quantification of the compound in biological fluids. Assume the target LOQ is 1 ng/mL.

Full validation to FDA preclinical guidelines should be performed initially for mouse and rat plasma.

• Characterize the in vitro stability of the compound in mouse and rat plasma at 37C. If significant decomposition is observed, similar studies should be conducted at 4C.

Assess the stability of the compound in frozen plasma and/or plasma extracts to determine appropriate sample handling and storage procedures.

• Determine the extent of protein binding of the compound at two concentrations in plasma from the species listed in the paragraph above.

• Pharmacokinetic studies should be conducted in mice (strain TBD) to characterize the plasma concentration-time profiles of the compound following single i.v. and oral bolus administration. A study design (timepoints, number of animals, etc) will be developed in conjunction with the Project Officer. A standard mathematical analysis of the plasma concentration-time data to yield half-life values, plasma clearance, AUC, bioavailability etc. should be included. Urine should be collected in selected animals for determination of cumulative drug excretion (e.fg., 16, 24 hr), urinary clearance, and possible identification of drug metabolites.

• Pharmacokinetic studies should also be conducted in F344 rats to characterize the plasma concentration-time profiles of the compound following single i.v. and oral bolus administration. Assume mouse PK data will be available to aid in study design. A standard mathematical analysis of the plasma concentration-time data to yield half-life

RFP/N01-CM-07014-39

Attachment 22, WA 3 values, plasma clearance, AUC, bioavailability etc. should be included. Urine should be collected in selected animals for determination of cumulative drug excretion, urinary clearance, and possible identification of drug metabolites.

As indicated in Part II of this form, please provide an estimate of the cost and effort required for this work assignment, as well as a description of your approach to the studies to be performed.

C. WA Leader: Fill in PI name

D. Deliverables:

(1) Interim data

(1) Monthly status reports

(2) Final WA report

E. Work Assignment Response Due Date: with proposal