This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: Induction of cytochrome P4503A (CYP3A) by Rifampin (RIF) will be partially counteracted by the inhibitory effect of Atazanavir (ATV) on CYP3A, and the net effect of co-administered ATV and RIF, under the higher dose condition at least, will result in ATV plasma pharmacokinetic (PK) profiles comparable to historical controls who received ATV 400 mg every 24 hrs. Tuberculosis is a leading cause of death worldwide due to a single infectious agent. It disproportionately affects persons living with HIV infection in resource-limited settings, creating an urgent need to study novel strategies to effectively treat persons co-infected with HIV and tuberculosis. The antituberculous drug RIF is a cornerstone of effective anti-tuberculous therapy. Unfortunately, studies to date have shown that co-administration of RIF lowers plasma levels of HIV protease inhibitors to subtherapeutic concentrations. A5213 is an open-label, single-arm PK interaction study of ATV and RIF. The primary objectives of this study are to investigate the effect of RIF on the PK of ATV and to assess safety/tolerability when ATV is co-administered with RIF. This will be accomplished by placing healthy HIV-1 seronegative subjects into one treatment arm with three treatment periods. The area under the curve (AUC) and common values of ATV when ATV and RIF are co-administered will be compared to the historic AUC and Cmin values, respectively, for ATV 400 mg, when administered once daily without RIF. The secondary objectives are to describe the PK of ATV when taken alone at a dose that is higher than is currently approved for routine clinical use; to explore the effect of RIF on the PK of ATV 300 mg twice daily; to explore the effect of ATV on the PK of RIF; to explore changes in cellular drug transporter expression when ATV is co-administered with RIF; and to describe the relationship between UGT-1A1 promoter alleles and serum bilirubin levels. During three sequential dosing periods each subject will receive: (1) ATV 300 mg every 12 hrs; (2) ATV 300 mg every 12 hrs plus RIF 600 mg every 24 hrs; then (3) ATV 400 mg every 12 hrs plus RIF 600 mg every 24 hrs orally. PK profiles will be assessed by serial plasma sampling over 12 hrs at the end of the first dosing period for ATV and over 24 hrs at the end of the second and third dosing periods for ATV and RIF.
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