The objective of these contracts is to acquire for the direct benefit of the Government, pharmacologic and toxicologic data on new drugs for the treatment of the Acquired Immunodeficiency Syndrome. The data will serve as the basis of the Government's filing for an INDA to institute human clinical trials. This data is collected in a series of toxicology and pharmacology studies and consists of the following. Analytical Phase: Drug identity analysis (e.g., IR, NMR, MP, MS, etc), validation of the procedures supplied by the NCI for dose concentration analyses and validation of the requisite methodology for assay of drug in biological fluids. Pharmacokinetic Phase: Plasma elimination kinetics will be determined in dogs and possibly in rodents after single intravenous and oral doses of drug. Oral bioavailability and plasma clearance rates will be determined in order to establish the dose required to produce the minimum viral inhibitory concentration (MIC) in the plasma for future toxicity studies. It may be necessary to determine bioavailability by other routes of administration such as ip or sc. The ability of the drug to cross the blood-brain barrier will be assessed in a 72 hour continuous infusion study in dogs. Toxicity Phase: For each drug, it will be necessary to establish a maximum tolerated dose (MTD) and organ toxicity in relation to its plasma concentration in both dogs and rodents. The following types of studies may be required in this phase: Single or multiple dose studies in rodents and dogs; Continuous administration to rodents via Alzet pumps and to dogs via infusion pumps; and Twenty-eight days of repeated administration of drug to rodents and dogs.
| Donzanti, B A; Kelley, J A; Tomaszewski, J E et al. (1995) Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat. Fundam Appl Toxicol 27:167-76 |
