Receive and Prepare Samples - Determine Basic Physical Characteristics for Pharmacokinetics and Pharmacodynamics of Antimicrobials in Animal ModelStore and record compounds. Archive a small sample of each compound from each lot. Determine the solubility and partition coefficients of the compounds provided in solvents. Determine the logP value for each of the compounds based on the data obtained.Prepare formulations of the compounds for in vivo testing in laboratory animals (e.g. aqueous, methylcellulose, cyclodextrin, or organic solvents) based on solubility data. Accurately prepare standard doses of the compounds for pharmacokinetic and pharmacodynamics (PK/PD) testing in mice. Routes of administration, e.g. po, iv, ip, and im will be established based on compound characteristics. Provide similarly prepared compounds and instructions to other laboratories that will perform in vivo efficacy determinations using mice infected with virulent organisms. Perform Screening Assessments of Bioavailability in Mice:Determine Pharmacokinetic and Detailed Bioavailability Measurements on Selected Candidate Therapeutic Agents:Perform pharmacokinetic and bioavailability assays on approximately 20 candidate therapeutic agents (compounds) per year utilizing primarily murine models as well as other animal models (e.g. rats or other rodents) as agreed upon with the P.O. Detailed protocols for each of the studies below, a through c, must be submitted to the P.O. for approval prior to initiating the study.Develop and validate appropriate analytical methodologies that are sufficiently sensitive to allow measurement and quantification of compounds and metabolites in body fluids and/or tissues of animals. Using these methodologies, determine appropriate pharmacokinetic parameters (e.g. half-life, volume of distribution, area under the curve, clearance, etc), perform one or multi-compartment analysis, and prepare reports and interpretations for the P.O.In vitro, determine induction or inhibition of P450 and/or other enzymes in murine and/or human enzyme systems in order to assist in the prediction of potential drug interactions.Develop and validate in vivo methodologies to test potential drug interactions of the compounds with a panel of specific drugs (e.g. rifamycin, protease inhibitors, erythromycin, and other antibiotics) to be approved by the P.O.Perform Pharmacodynamic Assays on the Candidate Therapeutic Agents (compounds).Test fluids and/or tissues from various compartments obtained from mice dosed over a range of concentrations for the ability to kill or inhibit the growth of microorganisms including, but not limited to: Mycobacterium species (e.g. BCG, or other rapid growing species), Staphylococcus aureus, or Streptococcus species. Determine the minimal inhibitory concentration (MIC), in vitro, of the compounds for the organisms mentioned in 4.a.Perform Pharmacodynamic Studies with Virulent Organisms:Perform similar pharmacodynamic studies on animals infected with virulent Biosafety Level-3 organisms such as Mycobacterium tuberculosis H37Rv or Erdman strain. Improve, standardize, and adopt new assays for determining the distribution and bioavailability and pharmacodynamics of the compounds in animal models.
