This Developmental Pharmacology Research application is composed of two component parts: 1) PK/PD response surface for antiretrovirals and 2) intracellular dideoxynucleoside analogues in target cells. Dr. Sheiner's section proposes three activities: (i) Simulation studies of pharmacokinetic (PK) monitoring of antiviral therapy. Cost effective use of (clinical) PK measurements requires that errors in timing of dose or blood sample acquisition not result in a """"""""noisier"""""""" relationship between """"""""exposure"""""""" and PK observation than between exposure and dose. This has not been adequately investigated for anti-HIV drugs. (ii) Development of population-based response-surface methods for interpreting PK and Pharmacodynamics (PD) of anti-HIV (especially combination) drug trials. Modern methods of population analysis and PK/PD modeling may allow more efficient use of data, dosage optimization, and improvements in trial designs. (iii) Collaboration with other ACTG investigators on population analysis of PK/PD data. Altered response in special groups (e.g. blacks, women, etc.) may depend on PK differences that can be discovered by analysis of PK data gathered during efficacy trials. Dr. Gambertoglio's section of the proposal will focus on two activities: (i) Develop methods for measurement of intracellular concentrations of zidovudine and its monophosphate, diphosphate and active triphosphate and lymphocytes and determine what relationship exists with extracellular plasma zidovudine concentrations. (ii) Determine the effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on intracellular concentrations of zidovudine and formation of the active triphosphate anabolite in peripheral blood monocytes/macrophages from patients with HIV infection receiving both drugs.

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