CORE--PHARMACOKINETIC ANALYSES

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The role of the Core D is to serve as a resource to this SPIRCAP project for pharmacokinetic analyses in order to attain expeditious Investigational New Drug (IND) approval of an identified human anti- cocaine antibody and second, to aid in the clinical assessment of its safety and efficiency. The goals of the analyses are to establish the pharmacokinetic basis for the antibody efficacy and recommend a dosing regimen for further clinical trials. The hypothesis of the proposed study is that by sequestering cocaine in plasma, a human anti-cocaine antibody significantly alters the pharmacokinetics of cocaine resulting in a marked reduction in the peak brain concentration and area under the concentration curve (AUC) of cocaine. Our preliminary studies on cocaine disposition in rats indicate that the plasma AUC, systemic clearance (CL/s) and the steady state volume of distribution (V/ss) of cocaine were 60 microgram.min/ml, 167 ml/(min.Kg) and 1.3 L/Kg, respectively, following an i.v. bolus dose of 10 microgram/Kg. During the first stage of the proposed pre-clinical pharmacokinetic investigations, following an i.v. bolus dose of 10 microgram/Kg. During the first stage of the proposed pre-clinical pharmacokinetic investigations, detailed studies on the influence of a murine anti-cocaine antibody (B4E10) on the plasma disposition and urinary excretion of cocaine and its metabolites, in rats will be evaluated (Project 2). To gain further insight into the antibody-mediated changes, this Core will conduct an in vitro investigation of cocaine disposition in human blood. Second, the disposition of several human anti-cocaine antibodies and their influence on the plasma clearance and brain uptake of cocaine will be evaluated (Project 2). The most efficacious antibody will be further screened for toxicity in accordance with FDA guidelines. Following IND approval of the human antibody, Phase I clinical trials will be initiated. This Core Unit will aid Project 3 in the pharmacokinetic evaluation of the antibody following single and multiple dose administration in humans. Subsequently, changes in the cocaine pharmacokinetics in the presence of the antibody will be examined. This will include an assessment of the plasma clearance as well as urinary and salivary excretion of cocaine and its metabolites in human subjects (Project 4). In general, the pharmacokinetic analyses will include determination of distribution and elimination half-lives, AUC, CL/s, V/ss and other parameters of the antibody, cocaine and its metabolites. The investigators have prior experience in such analyses and are well- qualified to aid this program project in the rapid development of a human anti-cocaine antibody.