Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics, and antiretroviral activity.

Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4(+) cell count of 266 cells/mm(3). Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).