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Date of Original Version



Pharmacy Practice


A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is effective for both acute and chronic infection in vitro and was evaluated clinically by continuous intravenous infusion administration. The minimum effective dose (the concentration required to completely inhibit viral replication) was determined in vitro in a population of uninfected (99%) and HIV-infected (1%) cells exposed to A-77003 by continuous infusion in hollow-fiber bioreactors. The production of infectious HIV and release of p24 antigen from infected cells were completely inhibited in cultures exposed to A-77003 at or above a concentration of 0.5 μM. Measurement of unintegrated HIV-1 DNA synthesis and flow cytometric analysis for cells expressing HIV p24 antigen demonstrated that the spread of HIV to uninfected cells was also blocked at 0.5 μM A-77003. Dose deescalation to 0.25 μM or removal of A-77003 resulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24. HIV produced after exposure to 0.5 μM A-77003 was noninfectious for a period of 72 h after the removal of the drug. Addition of 1 mg of α1-acid glycoprotein per ml to this in vitro system completely ablated the anti-HIV effect of 0.5 μM A-77003. These data suggest that determination of the minimum effective dose under conditions which simulate human pharmacodynamic patterns may be useful in determining the initial dose and schedule for clinical trials. However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.